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THE 

OPHTHALMIC    AND    CUTANEOUS 
DIAGNOSIS  OF  TUBERCULOSIS 

,THE    CUTANEOUS   AND    CONJUNCTIVAL    TUBERCULIN 
REACTIONS    ACCORDING    TO    v.    PIRQUET 
AND    WOLFF-EISNER) 

TOGETHER    WITH    A 

Discussion  of  the  Clinical  Methods  for  the  Early- 
Diagnosis  of  Pulmonary  Tuberculosis 

BY 

Dr.     ALFRED     W0LFF=EI5NER 

A   PREFACE   BY   PROFESSOR   H.   SENATOR 

AND   AN 

INTRODUCTORY    NOTE     TO     THE     ENGLISH     READER 

BY 

C.    THEODORE    WILLIAMS,    M.V.O.,    M.D.,    F.R.C.P. 

Consulting  Physician  to  King  Ediuard  VII.  Sanatorium  and  the  Brompton  Hospital ; 
Vice-President  of  the  International  Central  Bureau  for  the  Prevention  of  Consump- 
tion ;  Vice-Cliairmnn  of  the  National  Association  for  the  Prevention  of  Ccmsumption 

TRANSLATED     FROM     THE     GERMAN     BY 
BERNARD    I.    ROBERT 

With  2  Coloured  Litho  Tables,  11  Curve  Tables,  15  Reproductions, 
AND  Numerous  Curve  Figures  in  the  Text 

NEW    YORK 

WILLIAM     WOOD     AND     COMPANY 

MCMVIII 


RD'TAl'THC 


3'JS»t43 


3  D  A  "^  r 


INTRODUCTORY   NOTE. 


All  means  which  tend  to  promote  the  early  diagnosis  of 
tubercle  in  its  various  forms  are  very  acceptable  to  the 
clinician,  as  there  is  no  doubt  that  the  chances  of  arrest  of 
tuberculosis  depend  largely  on  its  early  detection. 

Though  great  things  have  been  accomplished  by  the  aid  of 
physical  signs,  of  sputum  testing,  of  radiography,  and  other 
modes  of  examination,  there  is  room  for  improvement  in  the 
methods  at  our  disposal,  and  in  the  fight  against  tuberculosis 
he  would  be  a  foolish  warrior  who  knowingly  would  neglect 
the  opportunity  of  adding  a  fresh  and  efficient  weapon  to  his 
armoury.  The  present  work  by  Dr.  Wolff-Eisner  on  Ophthal- 
mic and  Cutaneous  Diagnosis  is  a  valuable  addition  to  our 
knowledge,  as  it  describes,  firstly,  the  cutaneous  reaction  of 
Pirquet,  with  all  its  technique,  and  gives  the  author's  experience 
of  its  utility  ;  and  secondly,  it  famishes  full  details  of  the  con- 
junctival reaction,  which  has  been  generally  associated  with  the 
name  of  Calmette,  but  which,  on  very  strong  evidence,  is 
claimed  by  the  author,  as  a  co-discoverer  with  Calmette.  The 
book  is  full  of  original  work  and  is  a  most  conscientious  study 
of  the  two  reactions  in  hundreds  of  cases,  and  what  is  most 
valuable,  it  contains  a  comparison  with  the  results  of  other 
methods.  It  cannot  be  proved  as  yet  that  the  ophthalmic 
method  of  diagnosing  tubercle  is  infallible,  but  the  evidence 
of  this  and  other  works  testify  powerfully  to  its  future  value, 
as  a  handy  and  useful  instrument  for  the  many  labourers  in 

this  interestmg  field, 

C.  Theodore  Williams. 


PREFACE. 

Within  the  last  few  decades — after  its  treatment  had 
ceased  to  be  regarded  as  the  step-child  of  therapeutics, 
thanks  to  the  work  of  Brehmer  and  his  successors — medical 
interest  has  turned  to  the  treatment  of  tuberculosis  to  an 
altogether  unexpected  extent.  It  has  become  more  and  more 
recognized  that  this  disease,  so  much  feared  in  days  gone  by, 
in  reality  represents  a  very  fruitful  field  for  medical  activity  ; 
that  partial  and  even  full  recovery  in  a  clinical  sense  is  quite 
possible,  the  more  so  if  the  disease  is  recognized  early  and 
treated  at  once. 

Consequently  the  need  of  a  method  for  the  early  recog- 
nition of  tuberculosis  has  made  itself  more  and  more  felt, 
and  thus  not  only  have  the  existing  methods  of  diagnosis  of 
recent  years  become  more  elaborate  and  refined,  but  new  ones 
have  been  added,  such  as  the  demonstration  of  the  presence 
of  bacilli  and  Koch's  tuberculin  test,  the  Eontgen  examina- 
tion, the  cyto-diagnosis,  the  serum  diagnosis,  and  finally  the 
cutaneous  reaction  according  to  v.  Pirquet,  and  the  ophthalmic 
reaction  according  to  Wolff-Eisner  (and,  later,  Calmette). 

The  very  extensive  literature  already  existing  on  the 
subject  shows  with  what  zeal  these  new  methods  for  dia- 
gnosing tuberculosis  have  been  taken  up.  Even  the  very  latest 
reaction,  during  the  nine  months  it  has  been  generally  known, 
has  provoked  such  a  number  of  publications  in  the  most  varied 
journals  of  all  countries,  that  it  is  well-nigh  impossible  to 
acquaint  one's  self  with  all  of  them,  to  fully  test  the  value  of 
each  separate  view  concerning  the  theoretical  bases  under- 
lying the  reaction  methods,  and  to  find  out  which  is  the  best 
way  of  applying  them  practically. 

Now  the  book  of  Wolff-Eisner — who  is  pre-eminently 
qualified  to  expound  and  elucidate  this  .subject — comes  at  the 
right  moment.  Having  had  a  most  excellent  schooling  in 
bacteriology,  and  being  highly  versed  in  practical  medicine 
through  years  of  work  at  the  Berlin  Medical  University 
Clinic,  the    author   masters  the  earlier   as  well   as  the  more 


vi,  PREFACE 

recent  methods  of  investigation,  is  just  as  well  acquainted  with 
the  theoretical  bases  underlying  them  as  with  their  practical 
application,  and  takes  care  not  to  overrate  any  particular 
method,  including  his  own. 

By  demonstrating  that  hyper-sensibility  is  the  "'  basis 
underlying  immunity,"  and  also  by  his  investigations  into 
the  nature  of  hay  fever,  the  significance  of  albumin  poisons, 
of  endotoxins,  &c.,  he  has  shown  to  what  extent  bacteriology 
can  help  us  in  deciding  important  questions  of  pathology, 
prophylaxis,  and  therapy. 

In  this  way  his  book,  containing  a  rich  store  of  investiga- 
tions concerning  the  newly  disclosed  diagnostic  regions,  be- 
comes a  guide  pointing  with  clear  and  critical  vision  to  that 
which  is  most  important  and  of  the  greatest  essential  value 
in  the  great  mass  of  material  already  at  our  disposal  ;  it  is 
to  be  welcomed  both  by  the  technical  investigator  and  the 
practical  physician,  and  it  is  therefore  likely  to  have  a  wide 
circulation. 

H.    Senatok. 


TABLE  OF  CONTENTS. 


Introductory  Note 

Preface 

Introduction 


PAGE 

iv. 

V. 

1 


A. — General   Part. 

The  Development  of  the  Diagnosis  of  Tuberculosis.     Agglutination. 
The    Tuberculin    Diagnosis    of    Koch.     The     Need    for    other 

Methods              5 

The  Agglutination  Method  of  Arloing      ...         ...         ...         ...         ...  9 

The  Tuberculin  Method  of  Koch               10 

The  Application  of  Tuberculin  for  Diagnostic  Purposes           ...          ...  11 

Technique  of  the  Cutaneous  Reaction,  according  to  Pirquet  ...          ...  13 

Technique  of  the  Conjunctival  Reaction,  according  to  Wolff-Eisner  16 

Tubei'culin  Test  Preparations         ...          ...          ...          ...          ...          ...  21 

The  Course  of  the  Cutaneous  and  the  Conjunctival  Reaction             ...  22 

Unusual  Forms  of  Reaction            ...         ...         ...         ...         ...         ...  24 

The  Conjunctival  Reaction             ...         ...         ...         ...         ...         ...  26 

Contra-indications  for  the   Application  of  the  Cutaneous  and   Con- 
junctival Reactions       ...          ...          ...          ...          ...         ...          ...  30 

The  Result  of  the  Reaction  in  Tuberculosis  of  the  First,  Second  and 

Third  Stages  in  Healthy  and  in  Doubtful  Cases     ...          ...         ...  34 

History-  of  Some  Cases        ...         ...         ...         ...         ...         ...         ...  41 

Miliary  Tuberculosis             ...          ...          ...          ...         ...          ...          ...  43 

The  Behaviour  of  the  Reaction  in  Healthy  Individuals             ...         ...  46 

Post-mortem  Results            ...          ...          ...          ...          ...          ...          ...  51 

The  Behaviour  of  the  Reaction  in  Doubtful  Cases        ...         ...         ...  54 

The  Repetition  of  the  Reaction     ...         ...         ...         ...         ...         ...  62 

Nomenclature            ...          ...          ...          ...          ...          ...         ...         ...  66 

Opinions  of  Authors  on  the  Cutaneous  and  Conjunctival  Reactions ...  67 

Different  Cutaneous  Tuberculin  Reactions         ...         ...         ...         ...  74 

General  Reaction  in  the  Local  Applications  of  Tuberculin      ...         ...  76 


B. — Special  Part. 

The  Application  of  the  Cutaneous  and  Conjunctival  Reactions  in  the 

Diseases  of  Children     ...         ...         ...         ...         ...         ...         ...  77 

The  Application  of  the  Reactions  in  Dermatology         ...         82 

The  Application  of  the  Reactions  in  Ophthalmology    ...         ...         ...  87 

The  Application  of  the  Reactions  in  Gyniecologj'           ...          ...          ...  90 

The  Application  of  the  Reactions  in  Psychiatry            ...         ...         ...  91 

The  Application   of   the   Reactions   in  Veterinary  Science   and   the 

RcRults  obtained  in  Animals  with  the  Reactions    ...         ...         ...  92 


Vlll.  TABLE    OF    CONTENTS 

C. — Theoretical  Part. 

PAGE 

The  Comparative  Value  and  Significance  of  the  Cutaneous  and  Con- 
junctival Reactions       ...         ...  ...  ...         ...  ...         ...         97 

The  Reaction  in  other  Infectious  Diseases  101 

The    Pathological    Anatomy    of    the    Ciitaneous     and    Conjunctival 

Reactions  ...  ...  ...  ...  ...  ...  ...         ...       105 

The  Prognostic  Significance  of  the  Reaction       110 

The    Prognostic    Significance    of    the    Cutaneous    and    Conjunctival 

Reactions  ...         ...         ...         ...         ...         ...         ...         ...       112 

Tlieoretical  Part  of  the  Prognostic  Significance  of  the  Reaction         ...       118 

Further  Particulars  concerning  the  Mechanism  of  Tuberculin  Im- 
munity, and  of  Immunity  to  Tubercle  Bacilli         ...  ...  ...       126 

Observations    concerning   Tuberculin    Therapy    and   the    Treatment 

of  Tuberculosis  ...  ...  ...  ...  ...  ...  ...       136 

The   Historic  Development  of  the  Doctrine  of  Hypei-sensibility,  of 

Hyper-sensibility  Diseases,  of   Allergy,  and  the  Local  Reactions       141 

The  Outlook 148 

The  Clinical  Methods  of  Early  Diagnosis. 

The  Sputum  Investigation  ...         ...         ...         ...         ...         ...  155 

Thermometry  ...  ...  ...  ...  ...  ...  ...  ...  163 

The    Rontgen    Method    and    its    Application    for    the    Diagnosis    of 

Tuberculosis  ...  ...  ...  ...  ...  ...  ...  165 

The  Diagnosis  of  Tuberculosis  of  the  Bronchial  Glands  171 

The  Streak  Diagnosis  ..  ...  ...  ...  ...  ...  ...  177 

Percussion  of  the  Apices,  accoi'ding  to  Kronig  ...  ...  ...  177 

Auscultation  ...  ...  ...         ...  ...  ...  ...  ...  190 

The  Morphological  Examination  of  Exudations  :  the  so-called  Cyto- 

diagnosis  ...  ...  ...  ...  ...  ...         ...  ...  190 

The  Proteolytic  Fermentation  of  Exudations,  &c.         ...         ...  ...  195 

Inoscop3'         ...         ...         ...         ...         ...         ...         ...  197 


INTRODUCTION. 


The  fact  that  the  new  methods  of  diagnosis,  the  cutaneous 
reaction  of  Pirquet  and  my  conjunctival  reaction,  have  roused 
so  great  an  interest,  suggested  to  me  that  it  might  be  desirable 
to  more  precisely  define  my  standpoint  on  the  basis  of  personal 
experiences,  considering  at  the  same  time  the  numerous  works 
that  have  appeared  on  the  subject  ;  and  also,  incidentally,  to 
supply  the  practitioner  with  an  introduction  to  the  use  of 
these  methods  in  his  practice.  But  there  were  also  other 
reasons  which  led  me  to  do  so.  In  another  part  of  this  work 
the  reader  will  find  a  number  of  enthusiastic  references, 
especially  to  the  conjunctival  reaction,  which  medical  men, 
delighted  at  having  found  a  new  and  important  method  of 
diagnosis,  have  left  almost  entirely  uncriticised,  although 
opinions  have  been  expressed  by  writers  of  authority,  and 
several  writings  have  been  published  under  the  auspices  of 
important  institutions. 

No  one  has  ever  disputed  Pirquet's  discovery  ;  on  the 
contrary  its  predecessor,  the  cutaneous  puncture  reaction  of 
Klingmiiller,  has  never  been  referred  to  in  the  whole  of  the 
literature.  We  will  repeatedly  return  to  the  practical  and 
theoretical  importance  of  the  cutaneous  reaction.  Pirquet, 
before  making  his  method  public  property,  communicated  the 
same  to  me,  together  with  experimental  proofs,  and  thus  on 
the  day  of  his  lecture  I  was  already  in  a  position  to  confirm 
his  statements,  and  at  the  same  time  to  make  mention  of  the 
conjunctival  reaction. 

In  my  short  communication  concerning  this  method,  given 
as  an  observation  during  the  discussion  at  a  meeting  of  the 
"Berliner  medizinische  Gesellschaft "  on  May  1.5  (1907), 
I  hesitated  to  draw  far-reaching  and  even  very  evident  con- 
clusions which  would  have  increased  the  effect  the  commu- 
nication had  on  the  audience,  warned  as  I  was  by  the  fate 
of  many  a  predecessor,  and  especially  by  remembering  the 
conflict  that  is  still  going  on  to-day  concerning  the  diagnostic 
value  of  tuberculin.  In  order  to  draw  conclusions  of  a  reliable 
order,  I  thought,  it  would  be  necessary  to  base  them  only  on 
long-continued  clmical  observations  of  the  reactions.  Those 
1 


2  THE  OPHTHALMIC  AND  CUTANEOUS 

who  investigate  the  matter  after  me  were  less  reserved,  and 
in  the  course  of  days  and  weeks  I  read  definite  opinions 
concerning  the  "reaction  of  Calmette,"  as  my  reaction  had, 
in  the  meantime,  been  called  by  a  good  many  writers.  All 
this  could  not  induce  me  to  abandon  my  cautious  reserve, 
and  publish  immature  results.  Medical  men  and  investi- 
gators who  have  a  regard  for  thoroughness  will  not  allow 
my  conscientiousness  and  reservedness  to  be  interpreted  to 
my  prejudice,  nor  will  they  in  any  way  lessen  the  share  due 
to  me  in  the  matter  of  this  reaction. 

I  am  the  last  person  to  doubt  that  a  distinguished  and 
eminent  investigator  like  Calmette,  who  can  look  back  upon 
works  of  such  extraordinary  merit,  could  find,  and  has  found, 
quite  independently,  the  same  reaction ;  but  I  maintain  that 
I  have  carried  out  the  experiments  and  published  them  at  an 
earlier  date  than  he,  and  I  am  therefore  entitled  to  at  least 
equal  recognition,  which  was  withheld  from  me  by  Widal  and 
all  his  co-workers  in  the  case  of  the  cyto-diagnosis,  although 
at  that  time  my  position  was  equal,  or  rather  more  favourable, 
than  is  now  that  of  Calmette  with  regard  to  the  conjunctival 
reaction.  I  therefore  find  myself  obliged  to  protest  against 
the  reaction  being  frequently  designated  in  Germany  and 
France  as  "  Calmette's  test,"  a  protest  which  before  now  has 
been  put  forward  by  impartial  parties,  von  Pirquet,  Fritz 
Levy,  and  Stadelmann.^ 

First  of  all  I  must  contest  the  grounds  of  this  designation. 
Calmette  and  his  followers^  say,  that  there  is  no  doubt  that 
I  was  the  first  to  have  suggested  the  experiment,  but  that 
I  had  not  made  any  experiments  myself,  and  thus  to  Calmette 
belongs  the  honour  of  having  applied  it  to  clinical  work.  What 
may  be  the  thoughts  of  those  who  write  and  copy  this  ?  When, 
on  May  15,  I  made  the  communication,  four  weeks  before 
Calmette,  I  had  carried  out  experiments  upon  150  persons. 
I  declared  that  for  the  time  being  I  would  refrain  from 
drawing  even  obvious  conclusions  about  the  reaction,  in  order 
to  maintain  the  necessary  reserve,  and  especially  by  reason  of 
the  fact  that  there  are  differences  between  the  cutaneous  and 
conjunctival  reactions  which  it  was  first  necessary  to  clear  up. 


'  Pirquet,  Vers.  d.  Naturf.  u.  Aerzte,  Dresden,  1907 ;  Ges.  f.  Kinder- 
heilk.,  Ber.,  p.  34  ;  Fritz  Levy,  Ver  f.  innere  Med.,  Dec.  16,  1907. 
Stadelmann,  ibidem,  Jan.  6,  1908. 

-  Calmette,  Ac.  des  Sciences,  June  17,  1907 ;  Paris  and  Petit,  I.e. 


DIAGNOSIS    OF   TUBERCULOSIS  3 

But  iny  short  communication  shows  in  a  most  definite  manner 
that  I  have  suggested  this  method  for  chnical  purposes,  and 
that  I  have  made  it  known  for  chnical  use.  I  clearly  and 
distinctly  stated  :  The  method  is  of  diagnostic  as  loell  as  of 
prognostic  significance.  All  my  inclinations  point  in  a  clinical 
direction,  and  I  do  not  make  experiments  for  the  mere  sake 
of  experimentation,  but  ever  in  the  hope  that  they  may 
prove  of  clinical  value.  This  remark  applies  to  many  of  my 
works,  and,  as  in  the  case  of  hay  fever  and  other  diseases, 
this  reaction  is  a  proof  that  such  an  endeavour  may  sometimes 
lead  to  clinical  results. 

Thus,  in  this  w'ork  I  propose  to  warn  against  the  over- 
valuation of  my  own  method,  and  to  submit  a  critical 
description  of  what  has  been  attained  already  and  of  what 
it  is  possible  to  attain.  I  will  especially  guard  against  the 
over-valuation  of  the  conjunctival  method  at  the  cost  of 
the  excellent  cutaneous  method  of  Pirquet.  von  Pirquet, 
for  obvious  reasons,  has  not  experimented  very  frequently 
with  the  conjunctival  method,  and  most  of  the  other  investi- 
gators reject  the  cutaneous  reaction  and  only  avail  themselves 
of  the  conjunctival  method,  and  therefore,  thanks  to  the 
friendly  co-operation  of  Professor  Stadelmann  (for  whose 
help,  to  which  a  great  deal  of  the  success  of  this  method 
is  due,  I  here  express  my  deep-felt  gratitude),  I  am  practically 
the  only  one  who  has  had  the  opportunity  of  thoroughly 
investigating  by  means  of  both  methods  a  considerable 
amount  of  clinical  material. 

I  might  have  contented  myself  with  merely  collecting 
here  the  results  of  this  new  method.  But  both  these 
methods,  though  decidedly  excellent,  are  nothing  without 
having  been  clinically  tested.  To  indicate  this  I  have  also 
described  the  most  important  methods  of  early  diagnosis. 
From  this  we  may  see  how  many  good  methods  we  have 
at  our  disposal ;  of  these  many  are  still  far  too  little  in 
general  use.  During  about  eight  years  my  multifarious 
investigations  have  impinged  upon  the  region  of  earl}' 
diagnosis  of  tuberculosis  from  various  sides,  and  now  a 
curtain  seems  to  have  lifted  which  long  had  limited  my  out- 
look. It  now  appears  that  between  the  clinical-bacteriological 
method  of  tuberculin  diagnosis  and  the  cytological  condition, 
there  exists  a  closer  relationship  than  was  and  could  have 
been  formerly  supposed. 

If    a    medical   man — of   the    old    school — were    told    that 


4  THE  OPHTHALMIC  AND  CUTANEOUS 

nowadaj's,  armed  with  a  small  bottle  containing  a  dilution 
of  tuberculin,  one  would  venture  to  make  the  diagnosis  of 
tuberculosis  before  it  was  justified  by  clinical  investigation, 
a  picture  might  easily  arise  in  his  mind  of  a  time  when 
medical  art  had  become  practically  useless,  and  when  the 
medical  man  need  but  provide  himself  with  a  vaccinating 
lancet  and  a  number  of  diagnostic  fluids,  the  number  of  the 
latter  according  to  the  extent  of  the  practice  to  be  expected. 
There  is  some  truth  in  this  jest ;  there  certainly  does  exist 
a  danger  that  many  in  possession  of  such  useful  methods 
would  neglect  clinical  investigation.  This  little  work  is 
intended  to  obviate  this  danger,  by  showing  how  very 
necessary  seem  to  be  other  methods  of  diagnosis  even  to 
the  discoverer  of  the  reaction,  who  would  be  the  first  to 
have  a  right  to  over-esthuate  the  value  of  his  discovery. 

Some  of  these  other  methods  have  not  hitherto  been 
generally  applied  to  clinical  work.  The  criticism  which  I 
am  directing  against  my  own  method  will,  I  hope,  induce 
many  investigators  to  thoroughly  test  the  other  processes 
recommended.  Unfortunately,  neither  in  Germany  nor  any- 
where else  in  the  world  need  we  be  in  want  of  material 
for  testing  these  methods. 

The  possession  of  new  and  undoubtedly  good  methods- — 
firmly  based  on  aetiological  diagnosis — should  stimulate  the 
development  to  its  greatest  extent  of  topographical  diagnosis 
by  means  of  clinical  methods,  and  to  allow  these  methods 
to  become  the  common  property  of  all  medical  men,  just 
as  is  the  case  to-day  with  simple  percussion  and  auscultation, 
which  at  one  time  w^ere  the  property  of  but  a  small  school. 


DIAGNOSIS   OF   TUBERCULOSIS 


A.— GETs'ERAL  PART. 

THE  DEVELOPMENT  OF  THE  DIAGNOSIS  OF  TUBER- 
CULOSIS. AGGLUTINATION.  THE  TUBERCULIN 
DIAGNOSIS  OF  KOCH.  THE  NEED  FOR  OTHER 
METHODS. 

The  discovery  of  the  local  reactions  and  their  uses  for 
diagnostic  purposes  would  seem  to  indicate  the  beginning  of 
a  new  era  in  medicine.  It  opens  out  for  the  practitioner  new 
possibilities  with  regard  to  his  important  work  :  that  is  to  say, 
to  prevent  and  combat  tuberculosis,  and  also  other  infectious 
diseases.  Hardly  nine  months  have  elapsed  since  the  first 
communication  concerning  this  process  was  made  public,  and 
already  scientists  all  over  the  world  are  endeavouring  to 
perfect  the  methods  and  to  apply  them  more  and  more  to 
new  fields.  The  fact  that  in  a  short  space  of  time  more  than 
500  writings  have  appeared  on  the  subject,  together  with  the 
significance  attached  to  these  methods,  constitutes  a  proof  of 
the  immense  value  and  extent  of  the  work  accomplished 
nowadays  by  medical  investigators.  It  is  obvious  that  after 
so  short  a  time  problems  which  have  opened  themselves  up 
through  the  newly-revealed  reactions  have  not  yet  been  fully 
solved,  and  in  the  place  of  those  that  have  been  solved  new 
problems  have  sprung  up.  Yet  it  would  seem  that  the  time 
has  arrived  when  it  is  necessar}^  to  publish  what  has  already 
been  cleared  up,  and  institute  further  inquiries  in  order  to 
enable  the  increasing  number  of  those  whose  co-operation  in 
this  work  is  desirable  and  necessary  to  afford  us  their  help. 

The  question  whether  new  methods  are  needed  has  to  be 
decided  in  the  first  instance  by  results,  and  these,  without  any 
doubt,  appear  to  point  in  the  direction  of  such  a  necessity. 
The  diagnosis  of  tuberculosis  in  the  early  stages  (the  recog- 
nition of  which  is  of  the  highest  importance,  it  is  true,  is 
more  advanced  now  than  it  was  in  the  old  Viennese  school 
headed  by  Skoda  and  Traube.  But  it  has  not  yet  attained 
to  such  certainty  as  would  be  desirable  in  the  interest  of  the 
case.  It  was  often  thought  that  in  the  course  of  this  time 
progress  had  been  made,  and  it  is  just  now  the  twenty-fifth 
anniversary  of  the  famous  day  of  that  memorable  meeting  of 


6  THE  OPHTHALMIC  AND  CUTANEOUS 

the  Berlin  Physiological  Society,  to  which  one  often  hears 
allusion  made,  at  which  Koch  revealed  the  discovery  of  the 
tubercle  bacillus.  The  grand  solidity  of  his  discoveries  and 
the  flawlessness  of  his  arguments  will  for  ever  remain  a 
classical  example  of  scientific  publication.  Many  of  those 
present  claim  to  have  recognised  the  significance  of  the 
discovery  at  the  time  of  its  communication,  and  to  have  felt 
the  approach  of  a  new  era  of  exact  natural  science  in  clinical 
diagnosis.  The  tubercle  bacillus  attracted  the  attention  of 
everybody  to  such  an  extent  that  the  majority  of  the  investi- 
gators were,  so  to  speak,  hypnotised  by  it,  so  that  they  forgot 
all  else.  The  diagnosis  of  tuberculosis  was  based  only  on  the 
discovery  of  the  presence  of  tubercle  bacilli ;  where  bacilli 
were  not  found  no  tuberculosis  was  supposed  to  exist.  In 
this  purely  bacteriological  era,  clinical  investigation — which 
does  not  offer  any  specific  symptoms  by  means  of  which 
tuberculosis  could  be  discovered — may  sometimes  have  been 
somewhat  neglected,  and  when  we  bear  this  period  in  mind 
we  can  readily  understand  how  it  was  possible  that  of  late 
clinical  scientists,  such  as  Kronig,  for  instance,  have  said  with 
some  satisfaction  that  the  clinical  methods  of  investigation  in 
the  long  run  have  proved  to  be  superior  to  the  bacteriological 
and  again  have  become  recognised.  The  results  obtained  by 
one  method  may  for  a  time  cause  the  other  methods  to  be 
neglected,  but  the  difficulties  attached  to  diagnostical  synthesis 
will  always  result  in  the  reinstatement  of  the  old  methods, 
since  it  is  only  when  we  apply  all  diagnostic  methods  that 
are  at  our  disposal  that  we  can  obtain  a  clinical  picture 
which,  like  a  mosaic,  can  only  be  composed  of  stones  that 
supplement  one  another,  thus  approaching  the  truth.  In  this 
simile  we  find  at  once  the  full  answer  to  the  question  put 
above  as  to  the  necessity  of  a  new  method. 

The  recognition  of  the  true  value  of  the  presence  of  the 
bacillus  in  cases  of  tuberculosis  is  closely  connected  with  the 
sanatorium  movement  now  making  progress  in  Germany, 
which  for  the  first  time  makes  it  possible  to  collect  a  large 
amount  of  material  by  which  a  judgiuent  could  be  formed  as 
to  the  success  following"  attempts  to  cure  tuberculosis.  Before 
this  only  practitioners,  especially  those  holding  positions  as 
"  family  doctors,"  had  at  their  disposal  material  that  would 
be  of  use  in  settling  this  question.  But  no  general  use  had 
been  made  of  this  material,  probably  by  reason  of  its  being 
scattered  about. 


DIAGNOSIS    OF   TUBERCULOSIS  / 

At  present  there  is  a  current  of  thought  which  certainly 
undervalues  the  significance  of  sanatoria,  especially  as  schools 
for  hygienic  living  for  certain  sections  of  the  public.  But 
this  is  not  the  place  to  enlarge  on  this  subject.  This  dis- 
approval of  sanatoria  is  a  result  of  the  undoubted  fact  that 
the  hopes  put  into  them  have  not  been  fulfilled.  These  hopes 
were  to  some  extent  exaggerated,  but  one  is  bound  to  confess 
that  the  general  results  obtained  were  not  even  of  such  a 
nature  as  would  be  compatible  with  justifiable  expectations. 
Yet  these  sanatoria  have  not  been  built  m  vain,  if  it  were 
only  that  they  taught  us  that  the  curableness  of  tuberculosis 
was  absolutely  dependent  on  an  early  diagnosis.  The  earlier 
the  diagnosis  can  be  inade  out  the  better  the  chances  of  a 
cure.  Thus,  in  order  to  obtain  better  results,  the  methods  of 
diagnosis  had  to  be  improved.  In  the  beginning  it  was 
thought  to  be  undesirable  to  put  individuals — suspected  but 
not  yet  proved  to  be  suffering  from  tuberculosis— into  sana- 
toria where  they  would  be  in  danger  of  infection,  and  their 
admission  depended  practically  on  the  presence  of  tubercle 
bacilli  in  the  sputum.  But  on  the  basis  of  the  experiences 
gathered  in  those  very  sanatoria  this  view  has  generally  been 
abandoned.  It  was  this  basis  of  admission  which  was  the 
cause  of  the  unsatisfactory  results.  It  gradually  became 
recognised  that  tuberculosis  bacilli  in  the  sputum  did  not 
represent  the  initial  stage  of  the  disease.  This  is  not  difficult 
to  understand  if  we  remember  the  anatomical  conditions. 
Wherever  the  tubercle  bacillus  settles,  whether  in  small 
vessels,  or  in  the  submucosa,  or  in  the  intra-alveolar  tissues, 
it  cannot  possibly  at  first  reach  the  outer  world.  It  gradually 
forms  a  small  tubercle  which,  when  situated  in  a  small 
bronchus  or  bronchiole,  may  cause  an  atelectatic  collapse  of 
a  small  alveolar  region.  Tubercle  bacilli  can  only  appear  in 
the  sputum  when  the  bacilli  or  their  products  of  metabolism 
have  caused  a  caseation,  which,  when  it  breaks  through  the 
mucosa,  admits  the  tubercle  bacilli  into  the  bronchus,  and 
thus  into  the  sputum.  Everyone  who  is  acquainted  with 
these  conditions  can  realise  the  fact  that  a  fairly  large  number 
of  bacilli  must  be  present  before  they  can  be  detected  by  the 
comparatively  clumsy  microscopical  investigation,  especially 
since  in  fairly  early  stages  no  suspicious  lumps  are  as  yet  to 
be  found   which  allow  the  tubercle  bacilli  to  be  detected  so 

easily. 

The    distinction    made    lately    between    open    and    closed 


8  THE  OPHTHALMIC  AND  CUTANEOUS 

tuberculosis  simply  serves  to  indicate  whether  any  particular 
case  of  tuberculosis  is  one  of  mixed  infection  or  not.  In  a 
strictly  anatomical,  clinical,  and  bacteriological  sense  tuber- 
culosis is  to  be  regarded  as  an  open  disease  from  the  time 
onwards  that  tubercle  bacilli  appear  in  the  sputum,  and  from 
that  moment  the  door  is  open  to  mixed  infection.  Everyone 
knows  the  difticulty  experienced  in  diagnosing  catarrh  of  the 
apex  on  a  tuberculous  basis,  without  being  assisted  by  the 
presence  of  the  tubercle  bacilli- 
It  is  therefore  to  be  deplored  that  as  regards  this  impor- 
tant early  diagnosis  the  tubercle  bacilli,  which  represented 
the  greatest  advance  in  the  region  of  tubercular  diagnosis, 
are  of  little  use.  All  the  other  methods  dealt  with  in  this 
work  are  destined  in  the  first  instance  to  supply  a  substitute 
for  this  diagnostic  loss. 

For  cases  of  advanced  pulmonary  tuberculosis  there  is 
no  need  for  more  refined  methods,  since  those  that  are  known 
and  in  general  use  are  perfectly  satisfactory ;  the  results  of 
a  physical  investigation,  as  a  rule,  are  so  unambiguous  that 
doubt  can  only  be  entertained  in  very  rare  cases.  Also  in 
such  cases  tubercle  bacilli  are  to  be  found  in  the  sputum  with 
such  absolute  regularity  that  there  is  no  necessity  to  look  for 
a  more  refined  method.  We  emphasise  this  fact  here  because 
we  shall  see  later  on  that  the  most  refined  new  methods  fail 
to  operate  in  advanced  cases. 

On  the  other  hand,  the  less  frequent  forms  of  tuberculosis 
not  localised  in  the  lungs — tubercular  meningitis,  pleuritis 
tuberculosa,  peritoneal  tuberculosis,  and  especially  general 
tubercular  infection  (miliary  tuberculosis) — sometimes  present 
the  very  greatest  diagnostical  difficulties.  It  is  only  when  in 
possession  of  a  great  deal  of  material  that  one  can  realise 
how  often,  in  well-conducted  hospitals,  undiagnosed  miliary 
tuberculosis  is  found  to  exist  post  mortem,  how  frequently 
miliary  tuberculosis  is  wrongly  suspected,  and  how  many  a 
time  the  diagnosis — and  this  is  hardly  conceivable  by  a  be- 
ginning practitioner — wavers  between  typhoid,  sepsis,  and 
miliary  tuberculosis.  Here  we  are  already  a  long  time  in 
possession  of  another  and  very  real  form  of  ophthalmic 
diagnosis,  since  one  only  ventures  to  make  a  definite  diagnosis 
when  tubercles  are  found  in  the  fundus  oculi. 

Also  the  local  cutaneous  tuberculosis,  the  lightest  form 
of  tubercular  infection,  sometimes  presents  diagnostical 
difficulties  by  reason  of  its  similarity   to  a   number  of  other 


DIAGNOSIS    OF    TUBERCULOSIS  y 

cutaneous  affections.  The  [etiological  connections  between 
glandular  tuberculosis,  scrofula,  and  pseudo-leucocythsemia 
are  even  in  the  present  day  still  subjects  of  scientific 
discussion. 

For  all  these  cases  clinical  science  has  long  since  felt 
in  need  of  a  diagnostical  method  which  would  assist  the 
medical  man  in  his  clinical  diagnosis.  Since  the  discovery  of 
the  tubercle  bacillus  by  Koch,  only  two  methods  have  become 
known  which  were  of  assistance  in  the  diagnosis  of  tuber- 
culosis— the  method  of  the  agglutination  of  the  homogeneous 
tubercle  bacillus  culture  of  Arloing,  and  the  subcutaneous 
injection  of  tuberculin  for  diagnostical  purposes  by  Robert 
Koch,  Although  Koch's  method  is  the  earlier  one,  we  will 
first  deal  with  the  agglutination  diagnosis  of  tuberculosis, 
since  the  tuberculin  method  of  Koch  possesses  points  of 
close  contact  with  the  new  methods,  and  therefore  had  best 
be  dealt  with  together  with  the  latter. 

THE    AGGLUTINATION    METHOD    OF    ARLOING. 

The  agglutination  method  of  Arloing  is  based  chiefly  oa 
the  Gruber-Widal  reaction  of  the  agglutination  of  typhoid 
bacilli  by  means  of  immune  serum,  especially  by  means  of 
serum  of  typhoid  patients.  The  extraordinarily  favourable 
diagnostical  results  obtained  in  cases  of  typhoid  infection 
by  means  of  the  agglutination  experiment,  practically  in- 
vited a  transmission  of  this  method,  especially  since  it  was 
found  that  very  good  diagnostical  results  were  obtained  with 
it  in  the  cases  of  paratyphoid,  coli,  and  similar  bacteria. 
But  already  in  typhoid  certain  difficulties  are  encountered  in 
the  diagnostic  use  of  tbis  method.  No  former  attack  of 
typhoid  may  have  occurred — which  it  is  not  always  possible 
to  ascertain — in  order  to  allow  of  diagnostical  conclusions. 
Also  in  diseases  that  go  together  with  icteric  symptoms  we 
often  find  important  increases  of  the  index,  group  agglutin- 
ation occurs,  and  also  the  serum  of  a  normal  person  agglutin- 
ates, although  not  to  a  very  important  extent,  but  in  such 
a  manner  that  the  difference  is  only  a  quantitative  one.  No 
connection  can  be  found  between  the  degree  of  agglutination 
and  the  kind  and  course  of  the  disease  ;  some  people  with 
a  very  low  serum  index  may  overcome  the  infection,  whilst 
others  with  a  very  high  serum  index  may  not  be  able  to  do 
so,  and  may  die. 

To  this  there  is  added  the  difficulty  that  agglutination  is 


10  THE  OPHTHALMIC  AND  CUTANEOUS 

a  process  which,  without  forcing  the  matter,  can  only  be 
observed  in  movable  bacteria,  because  agglutination  consists 
in  the  conglomeration  of  the  flagella,  and  in  this  way  little 
heaps  are  formed.  But  this  difficulty  was  done  away  with 
by  the  discovery  that  agglutmation  can  also  be  observed  in 
the  dead,  and  therefore  flagellaless,  bacteria — the  agglutination 
of  dead  typhoid  bacilli,  according  to  Bordet  and  Ficker.  This 
fact,  which  at  first  sight  seems  rather  surprising,  becomes 
intelligible  by  understanding  that  besides  the  agglutinin 
proper  we  always  find  precipitin,  and  that  the  clarification 
of  the  fluid  containing  the  dead  bacteria  in  reality  constitutes 
a  process  of  precipitation  in  the  course  of  which  the  dead 
bacteria  are  drawn  to  the  bottom  in  clots.  (It  must,  however, 
be  mentioned  that  lately  the  method  of  Ficker  has  been 
violently  contradicted.  Schrumpf,  Miinch.  med.  Wochenschr., 
1907,  No.  51.) 

It  was  specially  difficult  to  make  sure  of  the  occurrence 
of  agglutination  in  the  case  of  tubercle  bacilli.  The  tubercle 
bacilli,  by  their  slow  growth,  have  the  peculiarity  that  they 
order  themselves  spontaneously  into  groups,  and  cultures 
of  this  kind  cannot,  of  course,  be  used  in  deciding  whether  an 
agglutination  process  has  taken  place  or  not.  This  only 
became  possible  after  success  in  obtaining,  by  means  of 
a  fairly  elaborate  technique,  cultures  of  agglutinable  tubercle 
bacilli,  spoken  of  as  the  homogeneous  culture  of  tubercle 
bacilli.  By  means  of  continuously  shaking  the  preparation 
during  its  growth  it  becomes  possible  to  obtain,  in  fluidic 
culture  media,  a  growth  in  which  the  bacteria  lie  singly 
and  thus  are  capable  of  being  agglutinated — that  is  to  say, 
precipitated. 

This  method  has  often  been  applied.  The  results,  though 
not  bad,  were  not  sufficiently  reliable  for  practical  purposes. 
Also  the  course  of  procedure  was  too  complicated,  and  there 
was  no  organic  connection  between  the  agglutination  and 
the  state  of  the  disease.  At  present  this  method  is  compara- 
tively little  used.  (See  Arloing  and  Courmont,  Ber.  des 
Kongresses  z.  Bek.  der  Tuberkulose,  Berlin,  1899,  p.  229. 
Beck  and  Kabinowitsch,  Deutsch.  med.  Wochenschr.,  1900, 
No.  25,  p.  400 ;  1901,  No.  10,  p.  145.) 

THE  TUBERCULIN  METHOD  OF  KOCH. 

Koch's  tuberculin  reaction,  on  the  other  hand,  has  found 
great  popularity,  and  to-day,  despite  all  opposition,  it  is  made 


DIAGNOSIS    OF   TUBERCULOSIS  11 

use  of  to  quite  an  enormous  extent.  The  discovery  by  Koch 
of  the  specific  tubercle  bacillus  toxin  inaugurated  a  new  era. 
The  excitement  in  the  medical  as  well  as  the  lay  world  was 
even  greater  than  that  created  at  the  period  following  the 
discovery  of  the  tubercle  bacillus.  The  cause  of  this  feverish 
excitement  lay  in  the  fact  that  at  the  time  it  was  hoped  (not  b} 
Koch,  though)  that  there  was  a  possibility  of  completely 
curing  tuberculosis.  The  question  concerning  the  significance 
of  tuberculin  as  a  cure  has  not  yet  been  settled,  but  we  do 
know  that  the  hopes  entertained  at  the  time  have  not  been 
fulfilled.  Nor  could  the  theoretical  basis  be  maintained  on 
which  originally  the  tuberculin  treatment  was  founded.  But 
it  will  be  seen  from  the  transactions  of  the  fourth  conference 
of  investigators  of  tuberculosis  in  May,  1907,  how  widespread, 
even  to-day,  is  the  therapeutic  appreciation  of  tuberculin.  It 
was  even  intended  to  form  a  society  of  adherents  of  the  tuber- 
culin treatment,  with  the  purpose  of  exchanging  experiences 
gained  by  the  application  of  this  so  frequently  opposed  remedy. 
This  project — which,  fortunately,  has  not  been  carried  out, 
since  a  fruitful  discussion  could  hardly  be  expected — at  all 
events  serves  to  show  how  difficult  it  must  be  to  judge  the 
therapeutic  results  of  tuberculin,  since  after  so  many  years 
of  arduous  investigation  its  adherents  still  find  it  necessary 
to  discuss  and  exchange  views  with  regard  to  the  remedy. 
Contrary  to  what  has  been  said  concerning  its  therapeutic 
value,  its  diagnostic  importance  is  not  to  be  doubted,  and  it  is 
hardly  an  exaggeration  to  maintain  that  this  discovery  stands 
at  the  beginning  of  the  diagnostic  science  of  tuberculosis,  and 
our  clinical  knowledge  concerning  the  distribution  of  this 
disease.  It  seems  to  have  been  the  mission  of  tuberculin  to 
completel}^  fill  up  the  gap  caused  by  the  loss  of  the  value  of 
the  tubercle  bacillus  for  purposes  of  early  diagnosis,  and  to 
constitute  an  extremely  fine  biological  method  by  which  to 
discover  even  the  very  first  stages  of  tuberculosis. 

THE  APPLICATION  OF  TUBERCULIN  FOR  DIAGNOSTIC    PURPOSES. 

Whilst  at  first  far  too  large  doses  of  tuberculin  had  been 
applied  for  diagnostic  purposes,  fairly  unanimous  points  of 
view  have  now  been  arrived  at.  Beginning  with  ^  to  1  milli- 
gramme, one  may  increase  the  quantity  to  3,  5,  or  even  8  milli- 
grammes, when  no  reaction  takes  place,  repeating  the  same  dose 
when    a   doubtful    reaction   occurs  (Koch,    Petraschky,    Beck, 


12  THE  OPHTHALMIC  AND  CUTANEOUS 

Max  Wolff,  MoUer).  Against  this  method  certain  objections 
may  be  raised,  to  which  we  shall  refer  later.  The  French 
clinicians  do  not  generally  use  larger  doses  than  ^  milligramme 
(Hutinel,  Grasset  and  Vedel,  Claisse,  Souques,  Cawadias,  Milian 
and  Sicard,  Labbe). 

"We  should  also  mention  the  method  of  Lowenstein  (and 
Ostrowsky),  who  repeats  the  same  small  dose  even  when  the 
result  of  the  reaction  is  a  negative  one.  In  this  case  diagnostic 
advantage  is  taken  of  the  hyper-sensibility  which  exists  in  the 
patient,  whilst  a  healthy  person  does  not  give  a  reaction  after 
the  second  or  third,  but  only  after  the  seventh  or  eighth 
repetition  of  a  small  dose. 

But  despite  the  indisputable  value  of  this  method,  the 
subcutaneous  injection  of  tuberculin  has  not  come  up  to  all 
expectations,  and  therefore  further  methods  for  the  early 
diagnosis  of  tuberculosis  were  sought.  The  reason  for  this 
disappointment  lies  in  a  series  of  important  shortcomings 
attached  to  this  method,  which  prevent  many  clinicians  and 
practitioners  from  making  use  of  this  reaction  in  human 
beings. 

In  the  first  instance,  certain  dangers  are  attached  to  the 
subcutaneous  tuberculin  reaction.  It  is  unnecessary  to  quote 
the  extensive  literature  on  the  subject  ;  their  existence  is 
undoubted. 

But  the  subcutaneous  injection  of  tuberculin  also  produces 
symptoms  of  disease  which,  it  is  true,  have  no  lasting  effect 
besides  causing  a  rise  in  the  temperature,  which  may 
frequently  be  very  considerable ;  lack  of  vitality ;  pains  in  the 
limbs;  various  symptoms  at  the  seat  of  the  disease;  and  severe 
headaches,  which  may  keep  the  patient  in  bed  several  days. 

All  this  renders  the  clinical  tuberculin  diagnosis  impossible 
in  practice  and  prevents  its  general  use  ;  quite  the  opposite 
is  the  case  with  the  new  local  reactions.  The  reason  that 
the  subcutaneous  tuberculin  injection  has  found  so  little  favour 
in  medical  practice,  lies  in  the  fact  that  the  diagnosis  depends 
on  a  rise  in  the  temperature.  That  is  to  say,  that  in  the  case 
of  people  whom  one  wishes  to  inject  subcutaneously  with 
tuberculin  for  the  purpose  of  diagnosis,  one  has  to  observe  the 
temperature  very  carefully  for  several  days.  For  this  purpose 
it  would  be  necessary  to  take  the  temperature  of  the  patient 
every  two  hours  after  the  injection.  The  taking  of  the  tempera- 
ture is  too  inconvenient,  and  this,  together  with  the  dangers 
referred  to,  is  the  principal  reason  why  the  subcutaneous 
injection  of  tuberculin  has  found  so  httle  favour  in  practice. 


DIAGNOSIS    OF   TUBERCULOSIS  I'S 

All  these  disadvantages  are  done  away  with  bij  the  applica- 
tion of  the  local  reactions.  They  do  not  expose  the  patient  to 
the  danger  of  being  injured  or  having  his  sufferings  increased  ; 
they  can  be  used  in  clinical  practice  ;  they  do  not  require 
a  tedious  observation  of  the  course  of  the  reaction  ;  and,  most 
important  of  all,  they  produce  reactions  just  as  specific  as  the 
subcutaneous  tuberculin  reaction.  The  results  put  forward 
in  this  book  justify  the  hope  that  the  subcutaneous  tuber- 
culin injection  can,  for  diagnostic  purposes,  be  replaced  by 
the  absolutely  harmless  local  reactions. 

In  the  following  chapter,  w^e  shall  at  once  proceed  to  deal 
with  the  local  reactions  ;  first  with  the  technique,  then  with 
the  practical  clinical  observations,  and  finally  with  the  theo- 
retical results. 

TECHNIQUE    OF    THE    CUTANEOUS    REACTION,    ACCORDING    TO 

PIRQUET. 

Instrunients. — The  cutaneous  inoculation,  according  to 
Pirquet,  may  be  performed  by  means  of  a  vaccinating  quill, 
vaccinating  lancet,  or  Pirquet's  raspatory.  For  the  investiga- 
tion of  large  numbers  the  use  of  a  platinum-iridium  instru- 
ment is  recommended.  This  inoculation  is  performed  in 
exactly  the  same  way  as  ordinary  vaccination  ;  before  inocu- 
lation the  skin  is  superficially  disinfected  with  alcohol  or 
alcoholic  ether.  The  danger  of  infection  during  and  after 
inoculation  is  very  slight,  since  it  is  only  very  rare  that 
pustules  occur,  as  is  the  case  in  vaccination  ;  therefore  a 
secondary  infection  is  excluded. 

In  order  to  successfully  perform  the  inoculation  it  is  not 
necessary  to  open  a  minute  blood-vessel  for  the  purpose  of 
producing  a  drop  of  blood.  The  opening  of  the  most  super- 
ficial lymph  passages  suffices  ;  this  is  clearly  proved  by  the 
fact  that  Moro  and  Doganoff  (by  the  cutaneous  tuberculin  test 
with  50  7o  tuberculin  salve)  and  shortly  after  Lignieres  and 
Berger  obtained  the  reaction  by  merely  rubbing  dead  tubercle 
bacilli  or  undiluted  (or  w4iat  acts  better  still,  concentrated) 
tuberculin  into  the  uninjured  skin  {Academic  des  Sciences,  Oct. 
28,  1907,  Paris,  and  Wiener  klin.  Wochenschr.,  1907).  One  can 
easily  understand  that  the  most  superficial  scarifications  are 
sufficient,  and  even  preferable,  because  a  blood  crust,  especially 
during  the  first  twenty-four  hours  after  vaccination,  may  ob- 
scure the  specific  reaction.  This  slight  operation,  which  is  lim- 
ited  to   the  most  superficial    epithelial  layers,  is  most  easily 


14 


THE  OPHTHALMIC  AND  CUTANEOUS 


performed  by  means  of  the  perforating  raspatory  of  Pirquet. 
It  is  necessary  to  slightly  stretch  with  the  other  hand  the 
sm-face  of  the  skin  where  the  operation  is  to  be  performed ; 
this  prevents  the  otherwise  relaxed  skin  from  being  torn 
during  the  boring,  or  rather  punching,  process,  which  would 
cause  unnecessary  pain.  Furthermore,  the  rasping  by  means 
of  Pirquet's  instrument  has  the  advantage  that  the  reaction 
following  on   the   inoculation  process  takes  a  circular  shape, 


Fig.  1. 
Vaccinating  perforator,  according  to  v.  Pirquet. 


whereas  the  reaction  after  an  ordinary  inoculating  incision 
would  naturally  take  a  long  oval  form.  Taking  the  perforator, 
which  is  made  heavier  at  the  handle  than  at  the  blade,  one 
presses  the  point  on  the  skin  and  performs  the  perforation 
by  rolling  the  handle  between  the  fingers. 

It  is  not  to  be  recommended  to  merely  moisten  the  inocu- 
lating apparatus  with  tuberculin,  as  in  ordinary  vaccination, 
where   the   quill   is    merely   moistened    with    the  vaccinating 


DIAGNOSIS    OF    TUBERCULOSIS 


15 


lymph ;  it  is  better  in  this  case  to  place  a  drop  on  the  skin 
and  to  make  the  scratch  or  move  the  perforator  in  this  drop. 
This  course  of  procedure  is  all  the  more  to  be  recommended 
since  the  inoculation  with  tuberculin  differs  from  ordinary 
vaccination  by  the  fact  that  in  the  former  there  is  no  danger 
of  implantuig  virus  that  is  capable  of  multiplying.  Most 
frequently  a  25  per  cent,  solution  of  Koch's  old  tuberculin  is 
employed  ;  but  I  refer  to  another  section  of  this  book,  where 
it  is  pointed  out  that  we  must  also  consider  the  possibility 


Fig.  2. 
Pipette  bottles,  according  to  v.  Pirquet. 


of  experimentmg  with  different  concentrations  and  other  tuber- 
culin preparations. 

Since  there  is  danger,  although  remote,  of  transmitting 
syphilis  from  one  human  being  to  another,  it  is  necessary  to 
make  the  platinum-iridium  vaccinating  lancet  glow  in  a  flame 
before  every  new  inoculation. 

Control  Inoculations. — As  Pirquet  has  mentioned  already, 
it  is  to  be  recommended  to  employ  a  control  inoculation. 
The  sensitiveness  of  the  skin  with  regard  to  traumatic  irrita- 
tions is  so  great  in  some  individuals  that  the  slightest  irrita- 
tion causes  a  reaction.     By  means  of  a  control  perforation  with 


16  THE  OPHTHALMIC  AND  CUTANEOUS 

a  drop  of  a  sterile  physiological  solution  of  common  salt,  or 
with  a  5  per  cent,  solution  of  glycerine  and  a  0"1  per  cent, 
one  of  carbolic  acid  (corresponding  to  the  concentrated  solu- 
tion employed),  it  is  possible  to  obtain  an  absolutely  correct 
picture  by  comparing  the  wound  reactions — which,  if  they 
appear  at  all,  are  very  minute — with  the  specific  reaction. 

In  the  case  of  inoculation  in  large  numbers,  I  should 
advise  the  use  of  two  inoculating  perforators,  one  for  control 
inoculations  and  the  other  for  tuberculin  inoculations,  be- 
cause on  account  of  its  great  heat-resisting  property  some 
tuberculin,  still  active,  might  be  brought  into  the  wound  by 
means  of  the  perforator,  and  thus  produce  a  reaction,  especially 
if  one  considers  the  minute  quantity  of  tuberculin  which  is 
necessary  to  produce  a  reaction. 

This  is  not  a  mere  theoretical  point.  We  have  seen  in 
thirty  inoculations,  performed  in  succession,  that  in  all  cases 
in  which  a  reaction  occurred  at  the  spot  of  inoculation  also 
a  slight  reaction  was  to  be  observed  in  the  control  spots. 
The  explanation  of  this  fact  was  that  only  one  lancet  was 
used  for  both  the  tuberculin  and  the  control  inoculation,  the 
instrument  having  been  heated  in  a  spirit  flame  between  the 
two  operations.  The  spirit  apparatus  was  filled  with  ordinary 
spirit  which  was  not  of  particularly  high  percentage,  the  flame 
was  sooty  and  did  not  cause  the  lancet  to  glow  in  a  quarter 
of  a  minute.  This  low  temperature  of  the  flame  was  the 
reason  why  the  heat  had  not  destroyed  the  tuberculin  that 
had  remained  on  the  lancet. 

TECHNIQUE    OF    THE    CONJUNCTIVAL    REACTION,    ACCORDING 
TO    WOLFF-EISNER. 

The  technique  of  the  conjunctival  tuberculin  diagnosis  is, 
if  possible,  even  more  simple  than  that  of  the  cutaneous 
inoculation.  One  proceeds  according  to  the  method  used  by 
all  medical  men  for  treating  conjunctivitis :  the  introduction 
of  a  drop  of  fluid  into  the  conjunctiva,  or  the  instillation  of 
atropine  for  diagnostic  and  therapeutic  purposes.  The  lower 
eyelid  is  drawn  down  and  the  drop  is  instilled.  But  since  it 
is  necessary  that  the  conjunctiva,  if  only  for  a  short  time,  be 
bathed  to  some  extent  in  the  fluid  instilled,  some  further 
measures  are  needed,  which  altogether  take  less  time  than 
their  enumeration  here.  In  some  individuals  the  cavity 
obtained   when   the   lower  eyelid    is  held  down  is   extremely 


DIAGNOSIS    OF    TUBERCULOSIS  17 

flat,  so  that  the  drop  easily  flows  out  again.  It  is  advisable 
that  the  head  should  be  held  somewhat  back,  in  order  to 
counteract  the  tendency  of  the  drop  to  run  out.  Then  the 
lower  lid  is  held  down  for  about  half  a  minute  in  order  to 
ascertain  the  bathing  of  the  mucous  membranes  in  the  solu- 
tion, and  then  the  patient  should  be  enjoined  to  remain,  his 
head  bent  back,  for  another  half  minute  without  closing  his 
eye,  in  order  to  prevent  the  drop  from  being  pressed  out  of 
the  eye  by  the  contraction  of  the  lids. 

Protective  Dressing. — In  cases  in  which  special  value  is 
attached  to  the  result  of  an  experiment,  it  may  be  advisable 
to  prevent  the  eye  being  rubbed  by  the  fingers,  and  causing 
a  traumatic  inflamed  irritation  or  secondary  infection.  This 
may  be  done  by  means  of  a  protective  dressing  of  the  eye, 
the  watch-glass  dressing  of  the  ophthalmologists  or  a  trans- 
parent celluloid  protective  cap — such  as  is  often  recommended 
in  vaccination — not  a  bandage  (monoculus)  which  itself  may 
cause  irritation.  In  our  numerous  investigations  such  pre- 
cautions have  not  been  necessary  ;  the  inclination  to  rub  and 
scratch  the  eye  was  but  extremely  slight. 

Hoiv  to  undertake  the  Beaction  in  Existing  Conjunctivitis. 
— The  self-evident  question  how  to  apply  the  reaction  in  a 
case  of  existing  conjunctivitis  has  to  be  answered.  In  our 
records  (see  tables)  we  have  carefully  noted  these  cases,  in 
order  to  exercise  special  care  in  making  use  of  the  results. 
If  both  eyes  were  equally  inflamed  no  difficulties  were  present, 
since  the  eye  not  operated  upon  afforded  a  comparison,  and 
thus  allowed  us  to  give  the  reaction  its  proper  value.  Fears 
expressed  by  Calmette,  for  instance,  concerning  the  use  of 
the  reaction  in  the  case  of  conjunctivitis  do  not  seem  to  have 
been  justified.  Since  conjunctivitis  is  of  extremely  frequent 
occurrence,  the  use  of  the  conjunctival  reaction  would  have 
been  very  much  impaired  if  these  theoretical  objections  of 
Calmette  had  been  justified,  and  if,  in  these  cases,  any  injury 
had  been  done  or  too  strong  a  reaction  had  been  observed. 
As  a  matter  of  fact,  the  instillation  of  tuberculin  had  not  the 
least  effect  on  the  conjunctivitis,  and  in  all  cases  where  a 
reaction  occurred  it  remained  absolutely  within  the  ordinary 
limits.  As  a  rule,  there  was  no  difficulty  in  recognising  the 
reaction  by  a  comparison  with  the  other  eye. 

But  greater  difficulties  are  encountered  where  the  con- 
junctivitis is  only  one-sided.  In  our  investigations  we  have 
fairly    frequently    met     with     one-sided     conjunctivitis,    and 

9 


18  THE  OPHTHALMIC  AND  CUTANEOUS 

we  have  found  that  it  is  more  frequent  than  one  would 
generally  be  inchned  to  suppose.  Since,  clinically  speaking, 
the  specific  reaction  only  manifests  itself  as  a  conjunctivitis 
in  those  cases  in  which  there  is  one-sided  conjunctivitis,  we 
have  no  eye  to  compare  with.  With  regard  to  such  cases,  we 
have  abandoned  our  principle  to  only  use  (in  order  to  avoid 
mistakes)  the  left  eye  of  the  patient,  and  have  instilled  the 
tuberculin  into  the  healthy  eye.  Now,  if  in  this  healthy  eye 
a  reaction  occurs  which  is  equal  to,  or  exceeds,  that  of  the 
inflammation,  we  may  without  hesitation  regard  the  reaction 
as  being  positive  ;  if  the  reaction  remains  weaker  the  decision 
is  more  difticult.  Yet  it  is  possible,  especially  if  one  pays  a 
great  deal  of  attention  to  such  cases,  to  decide  by  the  symptoms 
of  the  inoculated  eye  alone,  without  the  control  eye,  as  to  the 
positive  or  negative  result  of  the  reaction. 

The  above-described  measures  to  avoid  the  drop  of  tuber- 
culin solution  from  being  pressed  out  are  of  very  great 
practical  significance  for  ascertaining  the  result  of  the  reaction. 
This  has  also  been  pointed  out  by  Desplats  {Sociefe  des 
Sciences  Meclicales  de  Lille,  July  10,  1907),  Petit  (Ophthal- 
moreaktion,  1907,  Paris),  Masson  (p.  21),  and  Stadelmann 
(in  his  lecture  to  the  Verein  fiir  innere  Medizin,  on 
January  (3,  1908).  The  practitioner  who  has  only  occasion  to 
apply  this  reaction  in  a  few  cases  will  soon  have  his  attention 
directed  to  this  point. 

The  measures  of  precaution  have  to  be  very  carefully 
observed  in  cases  where  a  great  many  individuals  have  to  be 
examined,  and  the  few  cases  in  which  signs  were  found  of 
disagreement  between  the  tuberculin,  cutaneous  or  subcuta- 
neous reactions  on  the  one  side,  and  the  conjunctival  reaction 
on  the  other,  were  in  all  cases  easily  cleared  up  when,  under 
the  observation  of  these  precautionary  measures,  a  direct  and 
distinct  reaction  was  obtained  by  the  instillation  of  a  drop  of 
tuberculin  solution  into  the  other  eye.  We  shall  see  further 
on  that  a  repetition  of  the  experiment  in  the  same  eye  has  to 
be  absolutely  avoided  ;  therefore  in  the  same  individual  the 
experiment  can  only  be  repeated  once,  and  that  in  the  other 
eye.  From  this  it  is  evident  that  from  the  first  the  measures 
of  precaution  have  to  be  regarded  ;  these  measures,  fully 
applied,  yet  allow  the  reaction  to  be  performed  in  the  shoit 
space  of  time  of  about  a  minute.  (Compare,  however,  with 
the  chapter  dealing  with  our  experiences  in  cases  in  which 
the  instillation  was  repeated.) 


DIAGNOSIS    OF   TUBERCULOSIS  19 

Concentration  of  the  Solution. — We  make  use  of  a  solution 
of  Koch's  old  tuberculin  in  a  0"8  -gev  cent,  sterile  physio- 
logical salt  solution,  mixed  together  simply  by  means  of  sterile 
pipettes  and  brought  into  a  sterile  vessel.  It  is  to  be  recom- 
mended to  bring  the  amount  to  be  used  in  one  day  into 
a  watch  glass  and  from  there  on  to  the  conjunctiva  by  means 
of  a  pipette. 

As  the  original  solution  will  have  to  be  used  for  several 
days,  in  applying  the  conjunctival  reaction,  there  is  a  possi- 
bility of  conveying  septic  infection  from  the  solution  to  the 
conjunctiva  by  means  of  the  pipette,  the  contact  of  which 
with  the  conjunctiva  cannot  always  be  avoided.  According 
to  our  experience  the  development  of  bacteria  in  a  weak 
tuberculin  solution  renders  it  inactive  and  gives  rise  to  an 
important  source  of  errors,  to  which  w'e  must  call  attention 
(Stadelmann).  We  therefore  recommend  that  the  solution 
for  the  conjunctival  reaction  should  be  prepared  afresh  at 
least  once  a  week.  To  make  it  last  longer,  Eppenstein, 
instead  of  using  a  physiological  solution  of  common  salt,  sub- 
stitutes for  it  a  3  per  cent,  solution  of  boric  acid. 

Opinions  still  differ  as  to  the  correct  strength  of  the  solu- 
tion. At  first  I  made  use  of  a  10  per  cent,  solution,  whilst 
later  on,  at  the  request  of  Stadelmann,  I  carried  out  experi- 
ments with  a  1  per  cent,  solution.  Fritz  Levy  works  with 
2  per  cent,  and  4  per  cent.,  Eppenstein  with  ^  to  4  per  cent, 
solutions. 

The  difficulty  in  deciding  lies  in  the  fact  that  repetitions 
of  the  reaction  with  increasing  strengths  are  not  feasible  for 
reasons  to  be  dealt  with  later  on,  and  it  is  therefore  impera- 
tive to  decide  on  a  degree  of  concentration  which,  without 
causing  harm,  may  allow  of  an  exact  diagnosis  at  tlie  very 
first  application.  Since  I  did  not  see  any  evil  effects,^  even 
with  a  10  per  cent,  solution,  it  seemed  to  me  that  there  were 
no  objections  to  the  use  of  strong  solutions.  One  must  decide 
on  a  degree  of  concentration  (by  means  of  prolonged  efforts) 


'  A  case  of  which  I  was  informed  hy  Kronig,  of  suppuration  of  the 
Meibomian  gland  after  the  appHcation  of  a  1  per  cent,  tuberculin  solution, 
I  attribute  to  secondary  infection  or  bacterial  impurity  of  the  tuberculin 
made  use  of ;  the  possibility  that  injury  might  be  done  with  a  10  per  cent, 
tuberculin  solution  is  not,  of  course,  excluded.  A  strong  solution,  there- 
fore, is  only  to  be  applied  after  certain  precautionary  measures  have  been 
taken.  (See  the  chapter  deahng  with  contra-indications  and  with  its 
application  in  ophthalmology). 


20  THE  OPHTHALMIC  AND  CUTANEOUS 

which  will  give  a  distinct  reaction  in  affected  cases  without 
causing  a  rash  in  healthy  people  (donhtful  cases)  on  account 
of  the  strength  of  the  tuberculin  solution  used. 

As  mentioned  above,  we  have  carried  out  our  experiments 
with  a  1  per  cent,  solution,  and  were  completely  satisfied  with 
the  results  obtained :  they  were  neither  too  weak  nor  too 
strong.  Such  a  solution  prepared  from  the  ordinary  old 
tuberculin  of  Koch,  with  20  per  cent,  glycerine  added,  con- 
tains at  most  0"2  per  cent,  glycerine  and  0"005  per  cent, 
carbolic  acid,  an  amount  which  certainly  causes  no  symptoms 
of  irritation,  according  to  our  observations,  just  as  little,  in 
fact,  as  the  " fausses  reactions"  of  Calmette.  According  to 
Eppenstein  (Med.  KL,  1907,  No.  36)  and  Levy,  even  a  2  per 
cent,  glycerine  solution  does  not  cause  any  symptoms  of 
irritation. 

Fron:i  an  ophthalmological  point  of  view  the  occurrence 
of  a  reaction  after  the  application  of  a  2  per  cent,  glycerine 
solution  has  occasionally  been  observed,  but  these  cases  are 
so  rare,  and  then  only  limited  to  ophthalmic  patients,  that 
the  ordinary  medical  man  does  not  meet  with  them. 

We  find  that  one  of  the  chief  advantages  of  the  con- 
junctival method  in  the  form  we  recommend  lies  in  its  cheap- 
ness and  simplicity.  All  medical  men,  even  in  the  most 
distant  parts,  are  in  a  position  to  apply  this  method  without 
any  assistance.  Its  cost  varies  from  x^o  to  ^V  P^^'*'  of  a  penny 
per  reaction,  according  to  whether  one  prepares  the  solution 
oneself  or  has  it  prepared. 

This  point  brings  us  to  the  technique  of  Calmette.  In 
order  to  avoid  the  irritating  action  of  glycerine  on  the  mucous 
membrane,  he  recommends  the  use  of  tuberculin  precipitated 
by  alcohol.  He  takes  a  six  weeks  old  culture  of  tubercle 
bacilli  obtained  from  the  cow,  heats  it  or  destroys  it  in  the 
autoclave  at  a  temperature  of  110"  during  twenty  minutes, 
then  evaporates  down  to  one-tenth  at  a  temperature  of  80°  to 
90°  and  then  filters ;  finally  he  precipitates  by  means  of  95  per 
cent,  alcohol.  By  the  addition  of  a  small  piece  of  sodium 
chloride  the  precipitation  is  hastened  considerably.  He  then 
filters  through  a  filter  paper,  takes  the  precipitate  and  dries 
it  in  a  vacuum.  These  processes  are  repeated  twice  for  the 
purpose  of  further  purification ;  finally  a  whitish  powder  is 
obtained  which  is  free  from  glycerine,  and  is  supposed  not 
to  contain  any  resinous  or  waxy  substances,  but  which  yet 
contains  the  active  bacteria  (see  the  theoretical  part). 


DIAGNOSIS    OF   TUBERCULOSIS  21 


TUBERCULIN    TEST    PREPARATIONS. 

The  "  Institut  Pasteur  "  of  Lille  produces  the  preparation 
described  above  :  (1)  in  powder  form  in  doses  of  5  milli- 
grammes each,  to  be  used  for  the  preparation  of  a  1  per  cent, 
solution  by  adding  ten  drops  of  sterile  water  ;  (2)  a  sterilized 
10  per  cent,  solution  in  sealed  glass  tubes.  The  "  Hochster 
Farbwerke  "  have  lately  produced  a  similar  preparation  which, 
like  Calmette,  they  have  designated  "  test  tubercuhn." 

We  strongly  object  to  the  use  of  the  latter  preparation. 
A  number  of  strong  reactions  that  have  lately  become  known, 
and  which  might  discredit  the  whole  method,  are  to  be 
regarded  as  due  to  its  action.  According  to  Levy  the 
"Hochster"  test  tuberculin  is  too  strong,  and  according  to 
Wassermann  (oral  communication)  this  is  due  to  the  tuber- 
culin being  saturated  with  alcohol  and  the  solution  being 
calculated  not  on  the  basis  of  the  original  volume,  but  on  that 
of  the  weight  of  the  dry  substance.  100  c.c.  old  tuberculin 
yield  10  grammes  dry  substance  ;  if  this  is  employed  for  the 
preparation  of  a  1'/^  solution,  this  solution  in  reality  rep- 
resents a  10%  solution  according  to  the  standard  provided 
by  the  original  fluid  tuberculin. 

It  is  therefore  not  surprising  if  strong  reactions  are 
obtained  by  the  use  of  this  preparation.  The  so-called  1  per 
cent,  solution  has  to  be  diluted  about  ten  times. 

Nothmg  can  be  said  against  these  tuberculin  preparations, 
except  that  they  have  no  advantage  over  Koch's  old  tuber- 
culin, since  no  harm  has  ever  been  observed  by  us  to  have 
been  caused  by  glycerine,  if  one  uses  solutions  of  not  more 
than  0*2  per  cent,  concentration.  It  is  surprising  that  Cal- 
mette, without  stating  his  reasons,  should  have  made  use  of 
bovine  tubercle  bacilli.  Although  the  dissimilarity  between  the 
tubercle  bacilli  of  the  cow  and  those  of  human  origin  has  not 
yet  been  absolutely  proved,  according  to  Koch's  experiments 
the  bacilli  may  be  quite  separate,  and  this  hypothesis  must 
be  taken  into  account.  It  is  therefore  advisable  to  make  use 
of  solutions  prepared  from  tubercle  bacilli  of  human  origin, 
unless  one  intends  to  institute  investigations  concerning  the 
frequency  of  diseases  which  bovine  tubercle  bacilli  may 
produce  in  man. 

The  only  objection  w^e  have  to  these  other  preparations  is 
that  they  increase  the  cost  of  the  reaction  to  a  very  consider- 
able extent ;  whilst  it  is  just  the  cheapness  of  the  conjunctival 


22  THE  OPHTHALMIC  AND  CUTANEOUS 

reaction  and  the  simplicity  of  its  application  which  constitute 
one  of  its  greatest  advantages.  The  cost  of  a  reaction  by 
means  of  this  "  test  tuberculin  "  is  from  85 d.  to  Is.,  against 
tIo  to  £y  part  of  a  penny  when  old  tuberculin  is  used. 

Nor  can  Calmette's  idea  concerning  the  purification  of 
tuberculin  make  any  claim  to  originality.  Koch  himself  had 
already  prepared  a  tuberculinum  depuratum  by  adding  to  the 
tuberculin  one  and  a  half  times  its  volume  of  absolute  alcohol, 
and  by  repeatedly  washing  the  precipitate  that  had  formed 
after  twenty-four  hours  with  60  per  cent,  alcohol.  In  a 
similar  way  Klebs  prepares  tuberculinum  depuratum,  begin- 
ning also  by  producing  a  precipitate  by  means  of  alcohol.  He 
precipitates  the  fresh  tuberculin  by  adding  five  to  ten  times 
its  quantity  of  absolute  alcohol,  and  then  proceeds  with 
further  methods  of  purification  (quoted  after  Pick's  represen- 
tation of  antigene  in  Krans-Levaditi's  "  Hdbch.  der  Technik 
und  Methodik  der  Immun-Forsch.,"  Jena,  1907,  p.  364). 
Maragliano  has  also  prepared  an  aqueous  tuberculin  free  from 
glycerine. 

The  only  difference  which  exists  between  these  prepara- 
tions and  that  of  Calmette  consists  of  the  fact  that  in  the 
former  the  glycerine  is  removed  by  being  precipitated  by 
alcohol,  whilst  Calmette  does  not  allow  any  glycerine  to  act 
on  the  tubercle  bacilli.  However,  glycerine  is  the  extraction 
substance  Kar  e^o'x^rjv,  which  Koch,  after  very  elaborate  experi- 
ments, found  to  be  the  best  adapted  for  the  extraction  of 
tubercle  bacilli,  and  most  of  the  other  investigators  have  con- 
formed to  this  view. 

In  attaching  but  little  importance  to  the  purification  of 
tuberculin  we  are  of  the  same  opinion  as  Koch,  who  thinks 
that  the  purification  of  raw  tuberculin  is  not  of  very  great 
moment. 

THE  COURSE  OF  THE  CUTANEOUS  AND  THE  CONJUNCTIVAL 

REACTION. 

(1)  The  Cutaneous  Beaction. — In  consequence  of  the  inocu- 
lation after  about  an  hour  and  a  half  a  very  slight  redness 
appears  at  the  spot  of  inoculation  and  also  at  the  spot  of  the 
control  inoculation.  This  is  to  be  regarded  as  due  to  the 
slight  traumatic  irritation  caused  by  the  actual  performance 
of  the  inoculation.  As  a  rule  this  redness  disappears  after 
an  hour  or  two,  and  in  an  inoculation  leading  to  positive 
results  a  new  redness  appears  after  three  hours,  which  does 


DIAGNOSIS    OF    TUBERCULOSIS  23 

not  appear  on  the  control  spot.  The  redness  then  increases 
till  it  reaches  a  maximum,  which  in  different  cases  may  occur 
after  a  variable  number  of  hours,  very  frequently  after  between 
twelve  and  twenty-four  hours.  The  time  from  which  the 
reaction  may  be  said  to  take  its  course  varies.  In  judginc( 
the  degree  of  the  reaction  a  great  deal  is  left  to  the  judgment 
of  the  operator.  In  order  to  distinguish  this  degree  we  should 
advise  the  consideration  of  distinct  reactions  only  for  the 
purpose  of  diagnosis.  These  distinct  reactions  we  divide  into 
three  degrees  : 

(1)  Distinct  reaction ; 

(2)  Strong  reaction ; 

(3)  Very  .strong  reaction. 

Those  who  apply  the  cutaneous  reaction  often  will  not  be 
in  doubt  as  to  what  represents  a  very  strong  reaction ;  little 
difdculty  is  encountered  in  distinguishing  between  the  distinct 
and  strong  reactions.  The  reaction  can  occur  in  two  different 
ways.  Twenty-four  hours  after  having  reached  its  maximum, 
that  is  to  say,  altogether  after  forty-eight  hours,  it  may,  under 
certain  conditions,  decrease  to  such  an  extent  that  hardly  a 
sign  of  it  is  left ;  on  the  other  hand,  it  may  increase  in  the 
course  of  the  next  few  days.  We  attach  great  importance 
to  these  conditions,  and  we  have  therefore  in  our  tables 
recorded  in  each  case  the  course  of  the  reaction  during  the 
first  four  days.  The  type  of  reaction,  which  appears  quickly 
and  soon  disappears,  is  that  designated  by  the  French  as 
reaction  precoce  et  precise,  and  corresponds  to  the  reaction 
which  is  obtained  in  experiments  of  hyper-sensibility.  Here, 
too,  it  is  really  a  condition  of  hyper-sensibility,  which  is  dis- 
tinguished either  by  a  reaction  which  quickly  appears  and 
quickly  disappears,  or  by  one  of  excessive  intensity. 

At  about  the  spot  of  inoculation  the  following  effects  are 
observed  :  The  first,  as  a  rule,  is  an  injection  conditioned  by 
local  hypersemia  ;  then  follows  exudation,  which  causes  the 
spot  on  the  surface  to  appear  somewhat  in  relief.  This  can 
be  detected  better  by  touch  than  by  sight.  From  the  very 
beginning  the  exudation  often  is  so  tense  and  so  well  defined 
that  one  may  be  in  doubt  as  to  whether  this  is  not  an  infiltra- 
tion, and  as  a  matter  of  fact  very  frequently  the  original 
pomphus  changes  into  a  papule.  Since  we  make  so  important 
a  distinction  between  exudation  and  infiltration  in  the  employ- 
ment of  tuberculin  it  is  to  be  regretted  that  we  cannot  decide 
from  the  beginning  w^iether  we  have  to  deal  with  the  one 
or  the  other. 


24  THE  OPHTHALMIC  AND  CUTANEOUS 

It)  is  remarkable  that  in  many  cases,  and  also  in  any 
particular  case,  the  proportion  of  injection,  infiltration,  and 
exudation  varies,  and,  what  is  more  remarkable  still,  even 
during  the  course  of  the  reaction  any  of  these  may  show 
fluctuations,  which  may  easily  be  overlooked  in  clinical 
observation,  but  which  one  readily  appreciates  when  one 
endeavours  to  represent  them  by  curves.  For  instance,  the 
redness  may  surround  the  region  of  infiltration  in  the  form 
of  a  wide  halo,  and  then  it  may  suddenly  disappear  for  a  few 
hours,  appearing  again  in  the  form  of  a  halo  round  the  papule 
in  the  centre. 


UNUSUAL    FORMS    OF    REACTION. 

We  must  particularly  mention  some  unusual  forms  of 
reaction  which  we  have  noticed  in  a  very  few  cases.  In  one 
case  in  which  a  cutaneous  reaction  was  extraordinarily  strong, 
the  tense  papule  in  the  centre  gradually  softened  and  a  vesicle 
was  formed  filled  with  a  dull  grey  substance,  which  could 
hardly  be  distinguished  from  a  vaccine  pustule.  In  another 
case  in  which  no  ver}'  strong  reaction  took  place,  the  centre^ 
— which  did  not  exhibit  any  infiltration, — vesiculated,  showing 
a  moderately  injected  border  at  the  periphery,  which  shaped 
itself  into  concentric  rings,  and  these  gradually  paled.  At  the 
same  time  the  continually  increasing  centre  exhibited  desqua- 
mation, so  that  the  process  vividly  reminded  one  of  a  case 
of  herpes  tonsurans  (a  herpetiform  kind  of  reaction).  In  one 
case  herpes-like  vesicles  appeared  round  the  pustules ;  these 
dried  up  without  bursting,  il  am  convinced  that  a  great 
many  forms  of  reaction  will  still  be  discovered  and  described, 
especially  when  dermatologists,  who  have  had  a  great  deal 
of  practice  in  the  cognition  of  such  processes,  will  take  a 
greater  interest  in  these  forms  of  reaction.  As  a  matter  of 
fact  Bandler  and  Kreibich  have  described  different  forms  of 
cutaneous  tuberculosis  as  being  the  results  of  the  reaction 
(see  the  chapter  on  the  "  Application  of  the  Reaction  in 
Dermatology"  and  in  "Diseases  of  Children").  It  was  not 
mere  speculation  which  caused  us  to  determine  these  forms 
of  reaction.  Apart  from  the  fact  that  probably  a  distinct 
clinical  importance  has  to  be  assigned  to  each  form,  the 
different  reactions  that  follow  an  identical  inoculation  of  tuber- 
culin also  explain  polymorphism  of  the  tuberculous  affections 
of  the  skin. 


DIAGNOSIS    OF    TUBERCULOSIS  25 

Forms  of  Late  Reactions. —  Special  interest  attaches  to  a 
form  of  reaction  which  does  not  exhibit  a  subsidence  of  the 
symptoms  after  four  daj's,  but  on  the  contrary  shows  a  dis- 
tinct increase;  so  that,  for  example,  during  the  first  two  days 
there  is  a  distinct,  during  the  third  day  a  strong,  and  during 
the  fourth  day  a  very  strong  reaction.  Still  more  pronounced, 
and,  at  any  rate,  easier  to  diagnose,  is  another  form  of  late 
reaction  in  which  only  on  the  third  or  fourth  day  does  a 
reaction  take  place,  von  Pirquet  believes  such  a  reaction 
to  be  a  torpid  one,  and  does  not  exactly  know  what  sig- 
nificance to  attach  to  it.  We  (Stadelmann  and  myself) 
believe  it  to  be  of  great  importance  and  designate  it  as  late 
reaction.  Very  often  a  papule  of  long  duration  is  formed 
in  the  case  of  late  reaction.  This  may  also  occur  in  other 
forms  of  reaction,  although  it  would  be  rarer.  Such  a  late 
reaction  may  be  perfectly  unaltered  even  after  three  or  four 
weeks.  The  firmly  infiltered  papule  of  a  bluish-red  appearance 
reminds  one  of  the  early  stages  of  an  anatomical  tubercle. 

Lymphangitis  during  Cutaneous  Beaction. — There  are  but 
very  few  other  clinical  symptoms  which  have  to  be  men- 
tioned. In  only  one  case  have  we  observed  the  occurrence 
of  lymphangitis  with  swelling  of  the  cubital  glands,  but  this 
disappeared  within  three  days  without  further  symptoms. 
A  similar  observation  has  been  made  by  Kronig  in  his  experi- 
ments ;  in  investigating  the  case  I  found  a  slight,  but  very 
distinct,  retrogade  lymphangitis  in  which  the  redness  extended 
to  the  periphery.  In  these  cases  it  has  not  been  definitely 
ascertained  whether  during  or  after  inoculation  a  slight  infec- 
tion had  occurred,  such  as  may  sometimes  take  place  in 
vaccination,  or  whether  we  have  to  do  with  the  results  follow- 
ing a  very  strong  reaction.  This  latter  probability,  I  think, 
is  the  more  likely  one,  since  the  affection  appearing  after  the 
introduction  into  the  body  of  heterogeneous  albumin  without 
bacterial  infection  also  manifests  itself  as  fever  and  by  the 
swelling  of  glands. 

The  subjective  symptoms  caused  by  the  cutaneous  reac- 
tion are  extremely  slight.  A  few  times  itching  was  observed 
in  inoculated  patients,  which  became  more  troublesome  in 
long-persisting  forms  of  reaction.  But  this  cannot  be  of  great 
objective  importance,  since  it  has  never  been  observed  that 
patients  scratched  the  reaction  spots  ;  nor  was  itching  com- 
plained of,  but  its  occurrence  was  only  found  out  after  having 
directly  questioned  the  patients  as  to  its  presence. 


26  THE  OPHTHALMIC  AND  CUTANEOUS 

We  must,  however,  mention  the  appearnce  of  phlyctaenae 
which  were  observed  in  children,  following  on  inoculation. 
(See  chapter  on  this  subject.) 

After  the  injection  has  paled  down  and  the  infiltration 
disappeared,  the  skin  assumes  a  brownish-red  hue,  which  may 
for  a  long  time  remain,  finally  to  desquamate. 

THE    CONJUNCTIVAL    REACTION. 

There  are  very  few  remarks  to  be  made  with  regard  to 
the  conjunctival  reaction ;  after  a  period  of  from  six  to  twenty- 
four  hours  the  conjunctiva  reddens  slightly,  which  may  be 
recognized  by  comparison  with  the  other  eye.  Calmette,  and 
other  French  investigators,  as  also  Eppenstein,  maintain  that 
the  caruncle  reddens  first.  We  cannot  exactly  confirm  this 
observation,  but  the  fact  that  the  patients  complain  of  strong 
irritation  in  the  caruncle  after  the  solution  has  been  instilled 
on  to  the  conjunctiva,  speaks  in  its  favour.  Again,  since  the 
injected  fluid  is  evacuated  through  the  nasal  ducts,  and  is 
somewhat  obstructed  at  the  caruncle,  the  latter  remains 
longest  in  contact  with  the  tuberculin  solution,  and  thus  it 
could  be  understood  that  the  caruncle  would  exhibit  the 
earliest  and  most  marked  symptoms. 

First  Degree  of  tlie  Beaction. 

In  the  first  degree  of  the  reaction  no  more  than  a  redness 
of  the  conjunctiva  is  produced  ;  in  the  second  degree  the 
redness  is  more  intense,  and  goes  together  with  a  fibrinous 
exudation  of  mucus  ;  in  the  third  degree  all  these  symptoms 
are  increased  in  intensity,  whilst  at  the  same  time  there 
occurs  a  softening  of  the  conjunctiva  and  a  serious  infiltra- 
tion (chemosis).^  When  the  1  per  cent,  solution  of  old 
tuberculin  is  employed,  symptoms  indicating  the  third  degree 
are  of  extremely  rare  occurrence. 

In  second  and  third  degrees  of  the  reaction  one  often  finds 
that  the  follicles  of  the  conjunctiva  are  seen  quite  distinctly. 
The  strong  reactions  produce  the  symptoms  of  ordinary  con- 
junctivitis :  irritation,  photophobia,  and  a  feeling  as  if  foreign 
bodies  were  present.  In  all  but  a  few  cases  the  clinical 
symptoms  are  very  slight,  and  are  confined  to   a   feeling   of 


'  Very  rarely  slight  haeiuorrhages    are  observed   to  occur  on  the  con- 
junctiva (ecchymoses  Letulle). 


DIAGNOSIS    OF   TUBERCULOSIS  27 

heaviness  of  the  eye-Hds,  and  to  that  of  foreign  bodies  above 
referred  to ;  but  they  soon  disappear.  In  the  case  of  sensitive 
individuals  the  apphcation  of  boric  acid  fomentations,  and  in 
all  cases  the  use  of  a  drop  of  3  per  cent,  cocaine  solution,  have 
at  once  put  an  end  to  all  discomfort.  Under  certain  circum- 
stances a  combination  of  cocaine  and  adrenalin  (8  per  cent, 
and  1  per  mille.)  might  be  tried.  The  same  has  been  found 
useful  in  analogous  cases  of  hyper-sensibility  of  the  conjunctiva 
from  irritation  by  pollen. 

Secondary  Symptoms. 

Even  in  cases  in  which  highly  concentrated  solutions  were 
applied  there  was  no  sign  of  serious  consequences.  The 
symptoms  pass  away  in  a  few  days,  and,  as  a  rule,  entirely 
disappear  about  the  fourth  day.  A  late  conjunctival  reaction 
is  very  rare :  so  far  we  have  only  been  able  to  make  sure  of 
two  cases.  This  may  be  because,  when  there  is  only  a  slight 
opportunity  for  reaction  to  occur,  the  tuberculin  does  not 
remain  in  the  same  place  for  a  long  time,  and  also  because 
it  is  easily  absorbed  and  thus  enters  the  general  circulation. 
We  must  also  consider  that  the  tuberculin,  when  instilled  into 
the  eye,  does  not  retain  its  original  strength  for  long,  as  it 
is  quickly  diluted  by  the  lachrymal  secretion  which  follows 
its  application,  and  it  is  then  partly  carried  away  through 
the  nasal  duct. 

Nor  have  we  been  able  to  observe  long-continued  reactions 
on  the  conjunctiva;  but  it  is  necessary  to  pay  further  attention 
to  this  point,  since  Cohn  has  observed  reactions  lasting  up  to 
a  fortnight  {Berliner  klin.  Wochenschr.,  1907,  No.  47). 

As  mentioned  above,  unfavourable  secondary  symptoms  ^ 
have  never  been  observed.  One  may  safely  assume  that  up- 
wards of  10,000  cases  have  been  reported  on  up  to  the  present. 
The  number  of  those  treated  according  to  the  conjunctival 
method  is  probably  much  larger.  At  first  my  colleagues  ex- 
pressed their  doubt  as  to  whether  one  could  venture  to  attempt 
the  reaction  on  the  eye,  an  organ  of  such  vital  importance. 
From  the  very  beginning  I  expressed  my  firm  conviction  that 
no  danger  was  attached  to  the  reaction,  although  theoretically 
the  objection  could  be  raised  that  a  bacterial  infection  might 
be  superimposed  on  an  already  existing  conjunctivitis.  But 
my  experiences  with  hay  fever  enable  me  to  state  that  in  about 

'  See.  however,  the  chapter  on  Contra-Indications.  p.  30. 


28  THE  OPHTHALMIC  AND  CUTANEOUS 

200  cases  which  exhibited  the  severest  conjunctival  symptoms 
imaginable  during  eight  to  ten  weeks  continuously,  I  have 
never  observed  the  slightest  injury  to  the  interior  of  the  eye, 
not  even  when,  through  the  introduction  of  pollen  extract, 
the  process  going  on  in  the  conjunctiva  was  brought  to  a  most 
intense  degree  of  irritation.  The  symptoms,  therefore,  are 
limited  to  the  conjunctiva  ;  between  the  conjunctiva  and  the 
uveal  tract  there  exist  no  direct  communications,  or  if  they 
do,  they  are  of  very  slight  influence. 

Gommunicating  Tracts  in  the  Eye  hetween  the  Conjunctiva 
and  the  Uvea. 

I  am  indebted  to  my  friend  Dr.  Emil  Levi,  of  Stuttgart, 
the  oculist,  for  the  description  of  the  following  anatomical 
conditions. 

The  vascular  systems  of  the  conjunctiva  and  the  uvea  are 
distinct,  but  they  are  connected  by  means  of  the  rami  per- 
forantes  of  the  anterior  ciliary  arteries.  Together  with  the 
conjunctival  vessels  they  form  the  corona  vascularis  sur- 
rounding the  cornea,  the  so-called  marginal  network.  This 
connection,  however,  is,  comparatively  speaking,  insignificant 
(see  Leber's  table  of  the  vascular  course  in  Fuchs'  "  Lehrbuch 
der  Augenheilkunde ").  The  most  detailed  description  is 
found  in  Leber,  that  of  the  circulation  and  the  nutritive 
conditions  of  the  eye  in  Graefe-Samisch's  "  Handbuch  der 
Augenheilkunde,"  Second  Edition,  vol.  ii.,  2.  This  vascular 
communication  would  explain  the  ciliary  injection  we  once 
observed  in  a  patient  after  the  application  of  the  conjunctival 
reaction,  and  in  another  case  a  pericorneal  injection ;  it  not 
only  explains  the  occurrence  as  such,  but  also  the  rarity  of  the 
occurrence. 

A  transmission  of  the  reaction  to  the  interior  of  the  eye, 
apart  from  any  existing  vascular  connection,  might  also  be 
brought  about  by  means  of  lymph  spaces  and  lymph  passages 
(through  the  anterior  chamber  and  the  cornea),  since  drugs, 
such  as  atropin,  &c.,  so  much  in  use  in  ophthalmology,  can 
only  reach  the  interior  of  the  eye  in  this  way.  However,  in 
the  case  of  albuminoid  substances,  less  absorption  seems  to  take 
place  (compare  also  Leber  on  the  absorption  of  colloid  sub- 
stances through  the  cornea,  he.  cit.,  p.  387).  But  compared 
to  this  absorption,  the  one  that  takes  place  by  means  of  the 
circulation,  plays  a  role  of  even  less  importance  (see  p.  375), 


DIAGNOSIS    OF    TUBERCULOSIS  29 

From  a  practical  point  of  view,  the  absence  of  symptoms  in 
the  interior  of  the  eye  in  the  appHcation  of  the  conjunctival 
tubercuHn  reaction,  is  to  be  explained  by  the  fact  that  the 
amount  of  tuberculin  reaching  the  uvea  is  too  small  to  pro- 
duce any  irritation.  But  we  must  take  into  consideration 
that,  after  the  first  inoculation,  the  vessels,  especially  those 
of  the  interior  of  the  eye  (and  more  particularly  m  cases 
of  changes  in  the  cornea),  may  show  different  appearances 
with  regard  to  the  absorption  of  tuberculin. 

Communicating  Tracts  between  both  Eyes. 

Whilst  it  is  certain  that  communication  exists  between  the 
uveal  tracts  of  both  eyes — which  on  a  purely  clinical  ground 
can  easily  be  concluded  from  the  occurrence  of  panophthalmia 
— no  communication  exists  between  the  conjunctivse  of  the 
two  sides.  As  I  have  been  informed  by  ophthalmologists, 
Eversbusch  has  endeavoured  to  demonstrate  the  existence 
of  such  communications,  but  he  has  failed  in  his  attempt. 
Our  own  observations  are  in  harmony  with  this  view ;  it  was 
only  in  very  rare  cases  that  we  could  detect  a  trace  of  redden- 
ing in  the  other  eye.  In  order  to  explain  this  it  is  not  neces- 
sary to  assume  the  existence  of  a  communication ;  it  is 
more  probable  that  the  patient  with  his  finger  introduced 
a  trace  of  tuberculin  into  the  eye  that  had  not  been  tested. 
Cohn  has  observed  that,  when  the  instillation  is  repeated, 
there  occurs  not  only  a  strong  reaction  in  the  eye  in  which 
the  tuberculin  has  been  instilled  before,  but  that  the  eye  that 
had  not  been  tested  exhibits  hyper-sensibility  when  tuberculin 
is  instilled  into  it,  an  occurrence  which  Cohn  does  not  en- 
deavour to  explain.  It  is  difficult  to  interpret  this  fact  unless 
one  accepts  the  existence  of  a  common  tract.  Many  would 
not  feel  inclined  to  accept  as  an  explanation  the  occurrence 
of  a  sympathetic  transmission  along  nervous  paths,  the  less 
so  as  Cohn's  observations  have  not  to  do  with  the  transmission 
of  an  inflammation  but  with  that  of  a  condition  of  over-sensi- 
bility, so  that  no  other  explanation  remains  but  to  assume 
that  the  tuberculin  reaches  the  other  along  the  ciliary  nerves. 
But  before  framing  great  hypotheses  it  is  necessary  to  ab- 
solutely exclude  the  simplest  and  most  likely  explanation — 
that  of  transmission  of  tuberculin  by  the  finger — -by  means 
of  experimental  arrangements,  and  to  see  whether  in  that 
case  the  hyper-sensitiveness  of  the  other  eye,  described  by 
Cohn,  will  still  show  itself. 


30  THE  OPHTHALMIC  AND  CUTANEOUS 

We  may  assuredly  exclude  the  transmission  of  tuberculin 
along  a  tract,  since  no  direct  communication  exists  between 
the  conjunctivae.  On  the  other  hand,  according  to  ophthal- 
mologists, the  possibility  of  transmission  by  means  of  sym- 
pathetic irritation  along  the  ciliary  nerves — especially  in  an 
already  existing  condition  of  irritation — vt^ould  not  be  excluded 
(see  Schirmer's  "  Die  sympathetische  Augenerkrankung," 
Grsefe-Samisch  handbooks,  vol.  vi.). 

The  most  probable  explanation  of  the  accompanying  in- 
flammation of  the  second  eye  was  the  transmission  of  tuber- 
culin by  the  hand  of  the  patient.  This  possibility,  as  accounting 
for  the  existence  of  hyper-sensibility  of  the  other  eye  without 
preceding  inflammation  at  the  first  application  of  the  reaction, 
may  only  be  excluded  when  from  the  beginning  the  second 
eye  has  been  made  inaccessible  by  means  of  a  watch-glass 
bandage,  or  by  the  celluloid  protective  dressing  for  inoculation, 
which  I  have  recommended  before.  Other  dressings,  such  as 
the  much  used  monoculus,  cannot  be  recommended,  since  they 
themselves  may  cause  irritation.  For  this  special  purpose 
I  even  regard  the  celluloid  dressing,  which  admits  air,  to  be 
more  appropriate  than  the  ophthalmological  watch-glass  band- 
age, which  does  not  admit  air. 

The  occurrence  of  irritation  in  the  other  eye  is  too  rare 
to  require  systematic  bandaging  of  the  healthy  one.  On  the 
other  hand  it  would  conduce  to  exact  scientific  results  if 
the  eye  treated  with  tuberculin  were  in  this  manner  pro- 
tected from  being  touched. 

CONTRA-INDICATIONS   FOR  THE  APPLICATION  OF  THE  CUTANEOUS 
AND    CONJUNCTIVAL    REACTIONS. 

Contra- Lndications  for  the  Conjunctival  Reaction 
{Conjunctivitis) . 

The  discussion  of  the  contra-indications  follows  naturally 
on  the  short  anatomical  and  pathological  observations  of  the 
preceding  chapter.  For  this  reason  we  will  depart  from  our 
usual  custom  and  deal  first  with  the  contra-indications  of  the 
conjunctival  reaction.  Calmette  regards  conjunctivitis  as  a 
contra-indication  (see  our  remarks  on  the  Technique  of  the 
Reaction).  Although  also  Emii  Levi  {he.  cit.)  maintained, 
from  a  theoretical  point  of  view,  that  the  possibility  was  not 
absolutely  excluded  that  altered  conditions  of  absorption 
might  be  present  in  already  existing  inflammation,  and    that 


DIAGNOSIS    OF    TUBERCULOSIS  31 

in  such  cases  the  reaction  might  influence  the  uvea,  yet 
this  idea  proved  to  be  merely  a  theoretical  one,  since  in  all 
cases  of  conjunctivitis  no  symptoms  could  be  observed  in 
the  uvea,  nor  even  more  intense  symptoms  in  the  conjunc- 
tiva. I  will  not  neglect  to  mention  a  case,  communicated 
to  me  by  Kronig,  in  which,  eight  days  after  a  conjunctival 
reaction,  an  inflammation  of  the  Meibomian  gland  developed 
which  had  to  be  incised  several  times.  This  isolated  case 
can  hardly  be  regarded  as  a  contra-indication  in  any  direction 
whatever,  since  such  an  affection  may  originate  spontaneously 
as  well  as  follow  on  an  already  existing  conjunctivitis.  In 
the  manner  I  have  indicated  in  the  chapter  on  technique,  the 
solution  when  used  in  a  great  number  of  cases,  might  easily 
contain  bacteria  which  are  brought  from  one  eye  into  the 
other  by  means  of  the  pipette.  It  is,  therefore,  quite  probable 
that  a  case  like  this  is  not  to  be  attributed  to  the  tuberculin, 
and  may  possibly  be  prevented  by  taking  aseptic  measures. 

Wiens  and  Giinther  (Miinch.  med.  Wochenschr.,  1907, 
No.  52)  attribute  a  strong  reaction  to  an  already  existing 
conjunctivitis.  This  assumption  is  to  be  regarded  as  an 
erroneous  one,  since  strong  reactions  are  the  result  of  the 
use  of  strong  solutions  (see  "  Ausfiihrungen  iiber  Tuberkulin- 
Test,"  by  Hochst)  and  the  repetition  of  the  instillation  (see 
Wolff-Eisner,  Miinch.  med.  Wochenschr.,  1908,  No.  2).  In 
the  same  number  similar  communications  appeared  on 

Contra-Indications  in  Conditions  of  Irritation  in  the  Interior 

of  the  Eye. 

On  the  other  hand,  I  enjoin  great  care  in  dealing  with 
conditions  of  irritation  in  the  uvea  (iris),  &c.,  and  I  believe 
the  best  thing  to  do  is  to  ask  the  patient,  before  applying  the 
reaction,  whether  he  has  ever  suffered  with  his  eyes  or  has 
ever  been  under  the  treatment  of  an  oculist.  Cases  of  iritis 
are  not  so  frequent  as  to  in  any  way  mipair  the  diagnostic 
results,  and  I  should  not  like  to  bring  general  discredit  on 
the  conjunctival  reaction  by  reason  of  such  isolated  cases. 

However,  the  presence  of  tubercular  changes  in  the 
interior  of  the  eye  I  regard  as  an  absolute  contra-indication 
for  the  reaction,  that  is  to  say  in  the  ordinary  manner.  A 
minute  amount  of  tuberculin,  which  arrives  in  the  eye  affected 
with  tubercle,  would  produce  a  strong  reaction,  the  course 
of  which,  as  far  as  the  eye  is  concerned,  can  with  difliculty 


32  THE  OPHTHALMIC  AN]"*  CUTANEOUS 

be  predicted.  If  one  wishes  to  apply  the  reaction  in  any  case 
one  must  proceed  until  further  experience  has  been  gained 
in  a  way  similar  to  what  is  usual  in  tuberculin  therapeutics  ; 
that  is  to  say,  one  must  apply  so  small  a  dose  that  one  is 
niaster  of  the  reaction.  Instead  of  with  1  per  cent,  solutions 
one  might  perhaps  begin  with  solutions  of  1  :  100,000.  The 
conditions  for  the  tuberculin  diagnosis  in  the  eye  are  especially 
favourable.  Whereas  in  other  cases  one  can  only  once  apply 
the  reaction  to  the  conjunctiva  (see  chapter  on  the  Eepeti- 
tion  of  the  Reaction),  this  does  not  hold  good  in  the  case 
of  tuberculosis  of  the  interior  of  the  eye,  since  the  reaction 
need  not  be  judged  from  the  appearance  of  the  conjunctiva 
but  can  be  observed  in  the  tubercular  focus  itself. 

It  is  a  very  peculiar  fact  that,  in  their  attempts  to  produce 
focus  reactions  with  minute  doses  by  means  of  the  local  apph- 
cation  of  tuberculin,  ophthalmologists  have  not  discovered  the 
conjunctival  reaction.  In  internal  medicine  attempts  have 
been  made  to  advance  the  science  of  diagnosis  and  thera- 
peutics by  the  introduction  of  tuberculin  into  the  seat  of 
tuberculosis.  I  need  only  mention  here  the  diagnosis  by 
tuberculin  inhalations  and  the  unsuccessful  experiments  of 
pulmonary  injections.  In  the  case  of  ophthalmology  this 
therapeutic  application,  which  would  necessarily  have  led  to 
the  discovery  of  the  conjunctival  reaction,  would  have  been 
very  near,  since,  especially  in  ophthalmology,  reports  as  to 
the  very  favourable  results  of  the  subcutaneous  application 
of  tuberculin  in  cases  of  tuberculosis  of  the  eyes  have  fre- 
quently been  issued,  and  ophthalmologists  have  this  advan- 
tage over  other  medical  men  :  that  they  are  able  at  any  time 
to  see  the  reaction  of  the  focus,  and  need  not  draw  indirect 
conclusions  by  means  of  secondary  methods. 


Observations  in  Cases  of  Tuberculosis  of  the  Eye. 

(See  also  the  Special  Part,  on  the  Application  of  the  Reactions 
in  Ophthalmology.) 

I  almost  regret  not  to  have  published  before  this  these 
practically  self-evident  contra-indications,  w^iich  clearly  follow 
from  the  theoretical  bases  underlying  the  use  of  tuberculin, 
and  the  anatomical  structure  of  the  eye.  The}^  will,  I  hope, 
be  still  in  time  to  prevent  further  harm.  On  October  7,  1907, 
Kalt  communicated  a  case   to    the   Ophthalmological   Society 


DIAGNOSIS    OV    TUHKRCULOSIS  88 

of  Paris,  iu  which  he  had  apphed  the  reaction  to  a  patient 
suffering  with  corneal  opacity,  synechia,  and  opaque  refractin^^ 
media  ;  there  were  no  pericorneal  injections,  and  from  this  it 
could  be  concluded  that  the  changes  were  of  long  standing. 
On  July  '24  he  instilled  into  the  eye  one  drop  of  tuberculin 
1  :  100,  and  the  next  day  he  recognised  conjunctival  and 
pericorneal  injection.  After  six  days  the  sclerotic  focus  was 
enlarged  and  had  reddened ;  after  fourteen  days  the  iris  was 
in  a  very  irritable  condition,  the  injection  of  the  vascular  zone 
being  very  marked.  On  October  8  the  symptoms  had  come  to 
an  end  with  sclerotation  of  the  cornea.  Kalt  took  the  oppor- 
tunity to  repeat  his  experiment  in  a  ten-year-old  boy,  who  had 
small  tubercles  on  the  iris  and  in  the  corner  of  the  eye,  which 
up  to  then  had  followed  their  course  with  but  few  symptoms 
of  inflammation.  But  within  eight  days  the  reaction  set  up 
a  severe  inflammation  which  was  not  expected  after  the 
simple  aspect  it  had  worn  before.  Morax  attributes  the 
severe  symptoms  mentioned  by  Kalt  to  a  combination  of 
circumstances,  which,  however,  I  do  not  think  to  be  very 
probable,  though  I  do  agree  with  him  in  attributing  Terrien's 
discovery  of  the  occurrence  of  small  confluent  nodules  in  the 
conjunctiva  two  months  after  the  application  of  the  con- 
junctival reaction  to  the  possibility  of  a  drop  of  tuberculin 
exciting  a  latent  tuberculosis  of  the  conjunctiva,  although  it 
cannot  have  been  its  cause. 

I  am  inclined  to  accept  this  contra-indication,  although  in 
one  case  Citron  has  applied  this  reaction  in  a  case  of  tuber- 
culosis of  the  iris  without  the  iris  having  been  influenced,  and 
Stephenson  (British  Medical  Journal,  No.  2,442,  1907),  calling 
it  "  Calmette's  serum  reaction,"  as  also  Petit,  warmly  recom- 
mend this  method  for  diagnosing  the  tubercular  nature  of 
diseases  of  the  eye  (iridocyclitis,  sclerotitis,  choroiditis). 

Other  Secoiidarij  Symptoms  in  the  Application  of  the 
Conjunctival  Beaction. 

Eppenstein  recommends  a  solution  of  onl}'  i  per  cent,  in 
the  case  of  children  suffering  or  suspected  to  be  suffering  from 
tuberculosis,  in  order  to  prevent  the  occurrence  of  too  strong 
a  reaction.  He  has  observed  two  cases  in  which  tuberculous 
children,  after  the  application  of  a  1  per  cent,  tuberculin 
solution,  developed  a  slight  keratitis,  and  once,  in  a  boy  who 
liad  been  suffering  from  lichen  scrofulosum,  a  recurrent  kera- 
3 


34  THE  OPHTHALMIC  AND  CUTANEOUS 

titis  occurred  following  on  a  conjunctival  reaction.  In  these 
children  there  is  no  direct  connection  between  the  conjunctival 
reaction  and  the  keratitis  because  the  cornea  is  sufficiently 
near  to  the  reaction  that  is  taking  place.  Such  children 
frequently  suffer  from  keratitis  ;  a  direct  connection,  however, 
could  only  be  assumed  if  children  not  suffering  with  it  would 
develop  keratitis  after  cutaneous  inoculations.  All  this  con- 
cerns the  hypersensibility  with  regard  to  the  toxin  of  tubercle 
bacilli.  (See  Pfaundler,  Milnch.  Ges.  f.  Kinderheilk.,  ref. 
Mon.  /.  Kinderheilk.,  vol.  vi.,  No.  3;  Moro,  Wiener  Klin. 
Wochenschr.,  1907.  See  also  the  chapter  dealing  with  the 
application  of  the  reaction  in  the  diseases  of  children.)  For 
more  details  I  refer  to  the  special  part  on  the  Application  of 
the  Reaction  in  Ophthalmology. 


THE  RESULT  OF  THE  REACTION  IN  TUBERCULOSIS  OF  THE 
FIRST,  SECOND,  AND  THIRD  STAGES  IN  HEALTHY  AND  IN 
DOUBTFUL  CASES. 

Introductory  Remarks. 

It  is  advisable  to  deal  simultaneously  with  both  forms  of 
reaction,  the  cutaneous  and  the  conjunctival.  It  is  true  that 
this  way  of  dealing  with  the  subject  makes  it  more  difficult  to 
make  use  of  the  literature  on  the  subject,  since  it  is  onl}^ 
Mainini  (Milnch.  vied.  Wochenschr.,  1907),  who  so  far  (up  to 
January  1,  1908)  has  employed  both  reactions  simultaneously. 
For  this  reason  we  are  only  able  to  adduce  in  general  outlines 
the  results  obtained  b}^  other  writers  on  the  subjects  with 
either  of  these  methods.  Nor  do  we  intend  to  publish  every 
one  of  our  500  cases  with  their  diagnoses,  reactions,  and 
further  symptoms,  as  has  been  done  by  Petit  in  his  work  on 
ophthalmologic  reactions,  not  only  with  regard  to  his  own 
observations,  but  with  all  those  obtainable  in  the  literature 
on  the  subject.  This  would  be  altogether  unnecessary  for  our 
purpose,  for  which  it  is  of  greater  advantage  to  deal  with  the 
complete  symptoms  of  patients  at  the  time.  The  results  have 
been  taken  from  the  material  collected  by  Stadelmann,  as  well 
as  my  own,  with  the  kind  help  of  Drs.  Blume,  Mass,  Miinzer, 
Steinberg,  and  Teichmann. 

Actually,  the  number  of  our  observations  has  been  far 
greater  than  that  dealt  with  in  these  pages.  First  of  all 
I  have  omitted  my  own  150  experiments,  which  were  more 


DIAGNOSIS    OF    TUBERCULOSIS  85 

or  less  instructive,  as  also  all  patients  inoculated  after  Novem- 
ber 25,  because  the  publisher  was  rather  in  a  hurry  concerning 
the  appearance  of  these  communications.  These  later  in- 
oculations have  only  been  taken  into  account  in  so  far  as 
they  exhibited  peculiarities  not  in  accordance  with  the  general 
rules  ;  for  this  reason  the  conclusions  reached  would  not  in 
any  way  have  been  altered. 

Following  the  customary  rule  we  divide  the  tuberculosis 
patients  into  three  groups  : — 

First  Stage  :  Symptoms  at  the  apex  ;  unilateral  or  bilateral 
infiltration  of  the  apex ;  fever  absent  or  slight. 

Second  Stage  :  Infiltration  of  the  upper  lobes  ;  fever. 

Third  Stage  :  Considerable  infiltrations ;  formation  of 
cavities ;  hectic  fever  ;  decrease  in  weigfht. 

Our  initial  experiments  clearly  show^ed  that  there  were 
great  differences  in  the  three  stages  as  regards  the  manner 
of  reaction,  and  this  induced  us  to  retain  the  distinction 
between  these  stages  from  the  beginning. 

Tuberculosis  of  tlie  First  Stage. 

From  the  table  it  may  be  seen  that  out  of  20  tuberculosis 
patients  in  the  first  stage,  on  whom  the  cutaneous  reaction 
was  applied,  16  gave  positive,  4  negative  results.  In  5  the 
reaction  was  regarded  as  merely  indicative  of  the  disease, 
in  10  as  showing  the  existence  of  the  first  stage,  and  in  1 
of  the  second  stage.  We  found  that  the  majority  (about  80 
per  cent.)  responded,  but  the  reaction  was  not  a  verj-  strong 
one,  five  times  showing  merely  a  trace  of  the  disease,  which 
we  do  not  regard  as  a  pronounced  reaction.  The  second 
degree  of  reaction  occurred  only  once,  the  third  not  at  all. 
The  conjunctival  reaction  was  positive  in  14,  negative  in 
6  cases  (that  is,  positive  in  about  70  per  cent.)  ;  in  4  cases 
it  showed  traces  ;  in  4  it  gave  the  first  degree  ;  in  4  the 
second  ;  and  in  2  the  third.  The  cutaneous  reaction  failed 
in  4  patients  ;  the  conjunctival  in  6.  The  difference  is  not 
a  very  great  one ;  the  absence  of  response  in  these  two  cases 
may  be  attributed  to  errors  as  indicated  above.  But  it  is 
undeniable  that  in  cases  of  tuberculosis  of  the  first  stage  the 
conjunctival  reaction  is  inclined  to  be  the  stronger  of  the 
two,  so  that  this  reaction  frequently  is  the  more  distinct  one. 
These  figures,  however,  do  not  allow  us  to  draw  conclusions 
in  favour  of  either  reaction  (in  two  cases  the  cutaneous  reac- 


36  THE  OPHTHALMIC  AND  CUTANEOUS 

tion  is  more  marked  than  the  conjunctival,  whilst  in  four  the 
conjunctival  reaction  is  more  marked  than  the  cutaneous). 

Tuberculosis  of  the  Second  Stage. 

Of  26  cases  of  tuberculosis  in  the  second  stage,  18  re- 
sponded to  the  cutaneous  reaction,  and  15  to  the  conjunctival 
reaction.  The  cutaneous  reaction  gave  8  traces,  8  reactions 
of  the  first  degree  and  2  of  the  second.  The  conjunctival 
reaction  gave  one  trace,  9  of  the  first,  4  of  the  second,  and 
1  of  the  third  degree.  In  2  cases  the  cutaneous  reaction  was 
stronger,  in  3  cases  weaker  than  the  conjunctival  reaction. 
Again,  these  figures  do  not  permit  one  to  draw  definite  con- 
clusions as  regards  either  reaction. 

Tuberculosis  of  tlie  Third  Stage. 

Of  18  cases  of  tuberculosis  of  the  third  stage  only  3 
responded  to  the  cutaneous  reaction,  of  which  2  only  gave 
traces,  and  1  the  third  degree  of  the  reaction.  The  con- 
junctival method  gave  .5  positive  and  13  negative  results. 
Of  these  1  gave  traces,  2  were  of  the  first,  and  2  of  the 
second  degree  of  reaction.  One  of  these  latter  was  the  same 
patient  who,  in  the  cutaneous  reaction,  responded  in  the  third 
degree.  These  figures,  like  the  former,  do  not  show  any  very 
important  differences  between  the  two  reactions. 

Conclusio)is. 

These  results  allow  us  to  draw  the  following  important 
clinical  conclusions  :  the  reactions  call  forth  a  response  in  a 
great  number  of  cases  ;  but  the  reactions  are  not  in  proportion 
to  the  extent  and  the  degree  of  the  tuberculous  changes  that 
have  taken  place,  and  the  symptoms  caused  by  the  disease. 
The  strongest  reactions  observed  did  not  occur  in  clinicall}^ 
manifest  cases  of  tuberculosis,  but  in  cases  in  which  the 
patient  had  not  even  been  regarded  as  a  suspected  sufferer 
before  this  test  had  been  applied.  It  is  evident  that  in  the 
cutaneous,  as  well  as  the  conjunctival,  reaction,  the  number 
of  responses  decreases  in  percentage  as  the  tuberculosis  pro- 
gresses, and  they  fall  to  a  minimum  in  the  most  advanced 
cases,  the  very  severe  cases  of  the  third  stage.  The  tables 
would  wear  a  somewhat  different  aspect  if  we  would  retouch 
them  in  accordance  with  the  very  latest  data,  i.e.,  the  results 
of  post-mortem   examinations.     But  we  have  held  on  to  our 


DIAGNOSIS    OF    TUl^EllCULGSIS  37 

rule  and  only  registered  the  cases  as  they  have  been  reported 
upon,  according  to  the  inoculation,  by  the  investigator  in 
question,  w^ho  was  absolutely  neutral  as  to  the  results  of  the 
inoculations.  The  reactions  in  clinically  manifest  cases  of 
tuberculosis  have  this  in  common,  that  they  respond  to  the 
reaction  within  a  few  hours,  that  they  reach  the  greatest 
intensity  shortly  afterwards,  and  that  they  regress  just  as 
quickly.  Only  one  case  of  late  reaction  has  been  observed 
in  ()4  cutaneous  applications.  No  further  remarks  con- 
cerning the  course  of  the  conjunctival  reaction  are  neces- 
sary, since,  as  we  have  stated  above,  even  in  non-clinical 
cases  of  tuberculosis  late  reactions  have  but  very  rarely  been 
observed  on  the  conjunctiva.  Judging  by  the  slight  differ- 
ences between  the  figures  in  either  reaction,  it  can  hardly 
be  decided  whether  either  method  is  to  be  preferred  to  the 
other  (in  cases  of  tuberculosis).  We  can  only  form  a  proper 
judgment  when  we  can  take  the  other  categories  into  con- 
sideration, especially  the  reaction  in  healthy  individuals. 

In  tuberculosis  of  the  third  stage,  the  occurrence  of  the 
reaction  is  the  exception ;  our  statistics  give  '28  "pev  cent, 
(conj.)  and  15  per  cent,  (cutan.)  Most  of  these  only  give  traces, 
and  those  cases  in  which  the  reaction  was  a  strong  one  are 
exceptions  and  will  be  dealt  with  specially  later  on.  However, 
our  results,  which  I  believe  to  be  absolutely  reliable  and  in- 
disputable, are  altogether  contradicted  by  the  statistics  of 
A.  Frankel,  who,  in  tuberculosis  of  the  third  stage,  obtained 
positive  reactions  in  about  45  per  cent,  of  his  cases.  ^  (See 
Cohn,  Berl.  klin.  Wochenschr.,  1907.) 

The  statistics  of  Frankel  are  based  upon  comparatively  few 
cases,  and  the  difference  as  far  as  the  conjunctival  reaction 
is  concerned  (about  80  per  cent.)  is  not  so  great  as  would  have 
been  the  case  if  only  the  results  of  the  cutaneous  reaction  had 
been  considered.  For  this  reason  we  can  here  only  repeat 
our  advice  to  apply,  if  possible,  both  reactions,  and  generally 

'  Eppenstein,  who  did  not  distinguish  between  the  three  stages,  obtained 
positive  reactions  in  practically  100  per  cent.,  but  only  after  having  repeated 
the  instillation.  After  single  instillations,  out  of  40,  only  24  responded. 
Since  he  did  not  distinguish  between  the  stages,  we  may  not,  from  our 
point  of  view,  regard  his  material  as  reliable. 

So  also  Schenck  and  Seifert  (MiiucJi.  Med.  WoclienscJir.)  obtained 
response  in  100  per  cent,  of  their  patients  by  twice  repeating  the  conjunc- 
tival reaction.  At  the  first  instillation  the  responses  amounted  to  about 
80  per  cent.  (78-57  per  cent.). 


38  THE  OPHTHALMIC  AND  CUTANEOUS 

speaking — after  having  taken  into  consideration  all  possible 
secondary  influences — to  ascribe  a  higher  diagnostic  value  to 
the  conjunctival  reaction,  and  a  greater  prognostic  significance 
to  the  cutaneous  method.  Again,  in  considering  Frankel's 
figures,  one  must  consider  the  fact  that  he  proceeds  from  the 
theoretical  basis  that,  if  there  is  no  response  in  cases  of  evident 
tuberculosis,  this  is  to  be  attributed  to  a  faulty  reaction.  And 
since  the  reaction  has  so  great  a  diagnostic  significance,  we 
can  easily  understand  how  an  extremely  weak  reaction  may 
be  regarded  as  positive,  if  this  is  suggested  by  the  knowledge 
that  the  disease  is  present. 

The  figures  quoted  by  Klieneberger  in  the  Mi'inch.  Med. 
Wochenchr.,  1907,  No.  52,  and  used  by  him  to  criticize  the 
method,  agree  very  nearly  with  our  own.  (Negative  reactions 
about  50  per  cent. ;  out  of  7  cases  of  tuberculosis  2  were 
in  the  second  stage,  and  1  in  the  very  early  stage ;  out  of  4() 
cases  of  healthy  individuals,  8  [  =  about  16  per  cent.]  responded 
in  a  positive  way  to  the  conjunctival  reaction ;  when  repeated 
78  per  cent,  gave  a  positive  reaction.  This  agrees  with  Fritz 
Levy's  statistics.) 

These  figures  agree  to  a  surprising  extent.  The  fact  that 
he  draws  conclusions  which  I  regard  as  unjustified  does  not 
in  any  way  impair  the  similarity  of  the  results. 

From  the  result  of  our  observations — to  the  effect  that 
the  number  of  the  responses  decreases  as  the  disease  pro- 
gresses— it  is  evident  that,  when  it  is  ascertained  that  tuber- 
culosis does  exist,  the  result  of  the  reaction  enables  us  to 
conclude  a  posteriori  which  stage  the  disease  has  reached. 
However,  if  no  response  is  obtained,  this  does  not  so  much 
indicate    the    stage   of   the   disease '    as    the    absence    of    the 


Lenhartz  (Arztl.  Verein  Hamburg;  Milnch.  Med.  Wochenschr.,  1907) 
obtained   positive   cutaneous   and   conjunctival   reactions   in   22   cases    of 
tuberculosis ;    in    15   cases   they   were   varied  inversely    according  to   the 
strength  of  the  tuberculin  solution  employed. 

Letidle  (C.  B.  de  la  Societc  de  Biol.,  1907)  obtained  in  66  cases  (conj.  i 
63  positive  reactions,  of  which  50  +  +  +,  2  +-f -}-,  11  +,  3  -  (2  moribund, 
1  diagnosis  dubia). 

Schubert  (Ges.  f.  Xatur-  u.  Heilkunde,  Dresden,  MiincJi.  Med.  Wocheji- 
^chr.,  1907,  p.  2504)  obtained  out  of  19  cases,  17  positive  and  2  negative 
reactions. 

'  Eppenstein  and  other  writers  on  the  subject  were  not  able  to  find 
a  clear  connection  between  the  strength  of  the  reaction  and  the  stage 
of  the  disease.  Smce  it  is  true  that  such  a  connection  does  not  exist 
from  their  particular  point  of  view,  they  must  have  lost  sight  of  the  prog- 
nostic significance  of  the  reaction. 


DIAGNOSIS   OF   TUBERCULOSIS  89 

capacity  to  react,  and  this  enables  us  to  draw  important 
conclusions ;  for  a  number  of  non-reacting  cases  exist  in 
the  first  and  second  stages,  whilst  in  the  third  stage  we 
find  only  a  few  cases  in  which  reaction  is  positive.'  Now 
it  is  not  likely  that  a  first  stage  of  tuberculosis  could  be 
regarded  as  a  third  stage  simply  because  there  is  no  reaction, 
but  it  is  quite  possible  that  patients  in  whom  the  capacity 
to  react  is  absent  very  quickly  pass  from  one  stage  of  the 
disease  to  another,  and  it  is  this  point  which  has  been 
absolutely  justified  by  the  results  of  our  observations,  to 
which,  from  the  beginning,  I  have  directed  the  greatest 
attention.  It  is  extremely  important  to  diagnose  in  a  re- 
liable manner  tuberculosis  in  its  very  early  stages,  and  where 
it  is  only  suspected  ;  but  clinicians  have  no  difficulty  what- 
ever in  diagnosing  an  evident  case  of  tuberculosis  from  the 
first  to  the  third  stage.  It  is  of  much  greater  importance  to  be 
able  to  make  a  jjrognosis  in  a  simple  manner,  or,  putting  it 
in  other  terms,  to  be  able  to  recognize  whether  the  body  is 
in  a  condition  to  resist  the  progress  of  the  disease,  by  means 
of  treatment,  living  in  the  country,  suitable  climate,  sanatoria, 
seaside  residence,  6i.c.  The  stage  of  the  disease  offers  but 
few  indications  by  which  one  can  prognosticate  the  course  of 
the  disease.  An  initial  catarrh  of  the  apex  may  lead  to 
death  in  the  course  of  a  year,  whilst  a  case  of  advanced 
phtliisis  of  the  second  or  third  stage  may  allow  the  patient 
several  years  of  life  under  comparatively'  favourable  conditions. 
A  clinician  who  pointed  out  this  fact  called  the  attention  of 
his  pupils  to  the  possibility  of  such  a  lengthening  of  life  in 
the  case  of  tuberculous  patients  when  the  external  conditions 
were  of  a  favourable  nature  (see,  for  instance,  Striimpell, 
"  Lehrbuch  der  inneren  Medizin  "). 

At  last  we  begin  to  see  what  these  favourable  conditions 
consist  of:  viz.,  a  reactive  capacity  of  the  body,  which  may 
be  increased  by  favourable  external  conditions,  or  decreased 
to  a  minimum  by  unfavourable  conditions,  such  as  insufficient 
nourishment,  &c. 

'  It  must  be  mentioned  that  in  Kronig's  cases,  which  he  has  been  good 
enough  to  shoAV  me.  the  number  of  strong  reactions  in  the  third  stage 
was  greater  than  witli  us.  Almost  without  exception  the\-  were  cases  of 
advanced  phthisis,  which,  however,  had  taken  a  very  slow  coiu'se. 
Klieneberger  is  of  opinion  that  no  response  in  the  early  stages  of  the 
disease  indicates  some  defect  in  the  method,  whereas  we  regard  it  as  being 
one  of  its  most  important  assets. 


40  THE  OPHTHALMIC  AND    CUTANEOUS 

Now  it  cannot  be  denied  that  medical  men,  who  have 
had  a  great  deal  of  clinical  experience  with  regard  to  tuber- 
culosis, have  often  been  enabled  to  predict  the  course  of  the 
disease.  But  even  a  medical  man  with  the  greatest  ex- 
perience could  but  base  his  prognosis  on  a  very  long,  clinical 
observation,  and  it  will  readily  be  granted  that  before  such 
experience  had  been  attained  he  must  frequently  have  failed 
in  his  prognosis.  There  are  very  few  diseases  in  which  so 
many  living  witnesses  for  many  years  have  belied  the  doctor's 
hopeless  verdict  as  is  the  case  with  tuberculosis  of  the  lungs, 
and,  more  frequently  still,  a  favourable  course  of  the  disease 
is  predicted,  whilst  instead  the  victim  falls  an  early  prey  to 
the  scourge. 

It  is  not  to  be  doubted  therefore  that  a  reaction  which 
guides  our  clinical  judgment  with  regard  to  a  prognosis  of 
the  disease  along  the  right  channels  would  be  a  very  great 
boon,  and,  as  an  aid,  is  equal  in  value  to  a  diagnostic  method. 
In  order  to  prevent  misunderstanding  we  should  explain  that 
a  positive  reaction  indicates  the  existence  of  the  capacity  to 
react,  whereas  the  unresponsiveness  to  the  reaction  indicates 
a  lack  of  this  capacity.  We  will  refer  later  on  to  the  theoreti- 
cal significance  of  the  reactive  capacity,  or,  what  is  the  same, 
the  sensibility  or  insensibility  respectively.  I  will  only  say 
here  that,  according  to  our  observations,  the  absence  of  the 
reactive  capacity  is  in  all  cases  to  he  regarded  as  an  ominous 
sign,  whilst  the  positive  reaction,  on  the  other  hand,  merely 
indicates  the  reactive  capacity,  i.e.,  that  the  body  is  capable 
of  fighting  a  battle.  The  result  of  the  battle  does  not  depend 
on  the  one  factor,  the  reactive  capacity  alone,  but  on  a  great 
many  other  factors,  especially  on  the  virulence  of  the  bacteria 
in  question ;  but  the  reactive  capacity  in  this  struggle  is  a 
factor  of  importance  which  is  not  to  be  underrated.  And 
when  the  reaction  indicates  that  the  body  is  capable  of 
combating  the  infection,  we  are  justified  in  assisting  the  body 
in  its  struggle  with  all  the  means  at  our  disposal.  From 
the  figures  quoted  above  it  would  follow  that,  as  the  disease 
progresses,  the  reactive  capacity  of  the  body  decreases  ;  from 
80  per  cent,  in  the  first  stage  it  drops  to  about  60  per  cent, 
in  the  second  and  '20  per  cent,  in  the  third.  Now  I  should 
like  to  add  that  we  may  not  identify  the  quick  progress  of 
this  process  with  what  is  usually  understood  by  an  "  ad- 
vanced"  or  "inhibited"  disease;  as  already  stated,  a  process 
.showing  slight  changes  may  quickly  become  intensified,  whilst, 


DIAGNOSIS    OF    TUBERCULOSIS  41 

on  the  other  hand,  a  slowl}'  progressing  disease  may  in  the 
course  of  years  become  inhibited.  Therefore  the  decrease 
of  the  reactive  capacity  need  not  necessarily  correspond  to 
the  stage  which  the  disease  has  reached.  If,  notwithstanding, 
on  the  first  glance  there  seems  to  exist  a  remarkable  corre- 
spondence between  the  stage  of  the  disease  and  the  reactive 
capacit}',  this  has  to  be  attributed  to  the  fact  that  as  a  rule 
a  patient  with  catarrh  of  the  apex  resists  infection,  and  there- 
fore possesses  reactive  capacity,  whereas  in  the  patient  with 
advanced  pulmonary  symptoms  the  reactive  capacity  has  been 
exhausted  in  the  struggle,  and  the  disease  quickly  intensifies 
and  leads  to  death.  How,  in  the  course  of  the  infection,  the 
reactive  capacity  and  the  sensibility  gradually  cease,  we  will 
leave  to  be  dealt  with  in  our  theoretical  observations. 

It  seems  to  me  that  it  would  be  of  interest  to  quote  one 
or  two  especially  significant  histories  of  cases,  so  as  to  give 
some  example  of  the  prognostic  significance  of  the  reaction, 
and  to  point  more  particularly  to  such  cases  which  apparently 
to  some  extent  contradict  our  explanations  by  showing  a  nega- 
tive reaction  in  the  first  stage,  and  a  positive  reaction  in  the 
third.  For  this  purpose  I  make  use  of  our  own  material,  that 
is  to  say,  of  the  excellent  compilation  by  Professor  Stadel- 
mann,  to  whom  I  will  again  express  my  thanks  for  kindly 
allowing  me  to  use  it  in  this  publication. 

HISTORY    OF    SOME    CASES. 

We  will  first  of  all  deal  wdth  a  case  which,  clinically,  was 
regarded  as  being  in  the  first  stage  ;  negative  reaction  was 
obtained.  Ovinsk  (Pavilion  17),  admitted  on  October  1-5  :  very 
few  pulmonary  symptoms  ;  slight  ulcers  on  the  larynx. 

•21.x.  1907  1st        2ud       3rd       4th  day 


1st 

2ud 

3rd 

trace 

- 

- 

Cutaneous 
Conjunctival 

i.e.,  a  swiftly  passing  trace  of  redness,  lasting  only  one  day. 
The  reaction  did  not  agree  with  the  apparently  unimpor- 
tant lung  symptoms.  Percussion  sound  everywhere  normal  ; 
breath  sounds  vesicular  ;  over  the  right  apex  a  fairly  distinctly 
prolonged  expiration,  accompanied  by  a  few  very  dry,  crackling 
sounds.  This,  therefore,  according  to  the  clinical  examina- 
tion, was  a  simple  case  of  catarrh  of  the  apex.  To  this  was 
added  hectic  fever,  for  the  appearance  of  which  no  explaua- 


42  THE  OPHTHALMIC  AND  CUTANEOUS 

tion  could  be  found.  In  the  next  few  weeks  infiltration  and 
catarrhal  symptoms  appeared  over  the  two  superior  lobes  ; 
yet  the  clinical  result  could  still  be  regarded  as  insic;nificant. 
Notwithstanding  these  unimportant  clinical  synjptoms,  and 
despite  the  absence  of  diarrhoea  and  severe  bodily  pains,  a 
rapid  loss  of  strength  took  place  which,  after  about  six  weeks, 
led  to  a  high  degree  of  cachexia  and  to  the  formation  of  a 
great  hasmorrliagic  exudate;  the  patient  died  on  November  11. 
The  autopsy  gave  few  progressive  processes  in  the  two  superior 
lobes,  but  brought  to  light  an  extensive  tuberculosis  of  the 
pericardium  and  of  all  the  abdominal  organs,  as  also  enormous 
intestinal  ulcers. 

From  these  facts  it  appears  that  the  negative  result  of  the 
reaction  enabled  us  to  form  a  better  prognosis  than  the  clinical 
investigation  ;  also  that  the  contradiction  between  the  clinical 
lung  symptoms  and  the  reactive  capacity  enabled  us  to  draw 
the  conclusion  that  the  disease  in  the  lungs  would  either 
rapidly  intensify,  or  that  clinically  the  extension  of  the  disease 
in  the  lungs  had  been  diagnosed  inaccurately,  or  that  also  in 
other  parts  of  the  body  extensive  tuberculosis  existed.  This, 
therefore,  was  one  of  those  cases  of  the  first  stage  of  tubercu- 
losis in  which  the  altogether  negative  results  obtained  by  the 
cutaneous  reaction,  and  the  slight  traces  indicated  by  the  con- 
junctival reaction,  were  explained  on  post-mortem  examination. 

The  following  will  be  one  out  of  numerous  cases  in  which 
a  positive  reaction  was  obtained  in  the  first  stage  of  lung 
tuberculosis. 

A  patient  who  clinically  was  regarded  as  being  in  the  first 
stage  (Gade,  Pavilion  17),  showed  symptoms  of  an  infiltration 
of  the  left  apex,  slight  fever,  and  a  good  many  catarrhal 
symptoms  over  the  lungs.  In  the  sputum  bacilli  were 
found  ; — 

4th  day 


1st 

2nd 

3rd 

+ 

+ 

+ 

Cutaneous  +  +  +  +     decreasing 

Conjunctival 

This  great  difference  suggested  a  probable  mistake  in  the 
technique,  and  a  few  weeks  later  the  reaction  was  repeated 
on  the  other  eye.  A  distinct  positive  result  was  obtained  of 
between  the  first  and  second  degrees.  The  case,  therefore, 
was  to  be  regarded  as  of  fairly  favourable  prognostic  value. 

This  case  was  under  observation  for  three  months  ;  the 
patient  was  slightly  feverish  ;  sometimes  the  fever  disappeared 


DIAGNOSIS    OF   TUBERCULOSIS  43 

altogether  ;  the  process  in  the  lungs  sometimes  showed  signs 
of  regression  ;  progress  could  not  be  definitely  ascertained  ; 
the  patient  increased  in  weight  (6  lb.),  walked  about,  and  was 
fairly  well  subjectively  ;  there  was  but  little  coughing  and 
expectoration  of  sputum,  and  catarrhal  symptoms  were  few. 

Another  patient  in  the  first  stage  (Kleindienst,  Pavilion 
17)  gave  strong  conjunctival  and  cutaneous  reactions  with  a 
distinct  indication  of  infiltration  and  a  decided  and  direct  early 
reaction  (see  charts).  The  reaction  was  one  of  the  strongest 
observed.  The  circumference  of  the  papule  amounted  to 
"28  mm.  by  the  use  of  a  2-5  per  cent,  solution  of  old  tuberculin. 
The  disease  took  a  distinctly  favourable  course  ;  the  general 
condition  was  good  ;  the  patient  for  the  most  part  was  slightly 
feverish  (37-3H'C.)  ;  the  lung  symptoms  partly  regressed,  and 
he  gained  5  lb.  in  weight. 

From  the  result  of  the  reaction  we  may  conclude  that  the 
patient  had  reactive  capacity.  We  could  observe  that  it  was 
this  reactive  capacity  which  enabled  him  to  arrest  the  process 
during  his  stay  at  the  hospital,  and  to  improve  his  health. 


MILIARY    TUBERCULOSIS. 

AVe  have  not  had  a  very  great  deal  of  experience  with 
regard  to  the  result  of  the  reaction  in  cases  of  miliary  tuber- 
culosis. But,  according  to  the  literature,  the  reaction  is  a 
negative  one  in  most  cases.  We  have  observed  a  few  cases 
of  partial  distribution  of  miliary  tuberculosis,  especially  at 
the  base  of  the  brain.  In  one  case  (Stramm,  Pavilion  17)  in 
which,  according  to  the  clinical  diagnosis,  signs  of  extensive 
infiltration  were  found  in  the  left  upper  lobe,  together  with 
a  meningitis  tuberculosa,  the  reactions  were  negative.  As 
a  rule  a  negative  result  is  mentioned  in  the  literature,  also 
in  meningitis  tuberculosa  ;  but  this  result  seems  not  to  be 
a  constant  one,  since  in  another  case  under  our  observation 
the  reaction  in  meningitis  tuberculosa  gave  a  positive,  in  a 
third  case  again  a  negative,  result. 

In  children,  the  reactive  capacity  seems  to  last  longer 
(nearly  to  close  on  death  !)  in  miliary  tuberculosis  than  is  the 
case  in  adults,  where  it  disappears  some  time  before  death 
takes  place.  But  the  negativeness  of  the  reaction  is  only 
relative.  Experience  with  the  subcutaneous  injection  of 
tuberculin  shows  that  it  can  be  overcome  by  large  doses. 

von  Pirquet    obtained    the   following    results   in   children 


44  THE  OPHTHALMIC  AND  CUTANEOUS 

suffering  with  miliary   tuberculosis  {Wiener  klin.    WochenscJir., 
1907,  No.  88)  :— 


20 -10  days 

10  —  0  days  (oite  mortem 

9  + 

13   + 
13   - 

=  Positive  reaction.              —   =  Negative  react 

"lu  three  cases  the  decrease  in  the  reactive  capacity  could  be  definitely 
ascertained  ;  this  began  about  three  weeks  ante  mortem,  and  in  some  cases  it 
decreased  to  zero,  in  others  it  did  not  decrease  to  quite  that  extent,  whilst  in 
one  case  a  child  showed  strong  reaction  even  three  days  before  death."' 

The  course  of  those  cases  representing  progressive  pul- 
monary changes  of  stages  II. — III.  and  III.  which  have 
produced  a  distinct,  positive  reaction,  must  be  specially 
mentioned.  The  greater  number  of  such  cases  represent 
exceptional  conditions. 

Case  1. — Post  mortem  showed  but  slight  alteration  of  the 
lungs,  and  death  was  due,  not  to  phthisis,  but  to  amyloid 
degeneration. 

Case  2. — The  disease,  after  rapid  progress,  unexpectedly 
came  to  a  standstill,  and  took  a  favourable  course. 

Case  3. — Took  a  very  favourable  course,  and  suddenly 
died  of  haemoptysis. 

Cases  4  and  5. — The  disease  took  a  progressive  course 
despite  positive  reactions  (see  specifications  below). 

The  history  of  these  cases  is  very  interesting  and  instruc- 
tive (see  Stadelmann,  Deutsche  Med.  Wochenschr.,  1908). 

Case  1,  a  patient  in  the  third  stage  (Pavilion  1,  Giihlsdorf), 
gave  very  strong  cutaneous  and  strong  conjunctival  reactions. 

Post-mortem  examination  showed  very  severe  amyloid 
degeneration  of  intestines  and  kidneys.  Compared  with  this 
the  tuberculous  affection  of  the  lungs  was  but  slight,  since 
it  only  represented  stage  I. — II.  The  strong  reaction  in  this 
case  is  thus  easily  explained,  although  it  cannot  be  exactly 
shown  what  the  amyloid  degeneration  was  caused  by. 

Case  2. — A  young  girl  (Hein,  Pavilion  1  ;  second  stage  of 
tuberculosis  ;  under  observation  from  March  12  to  July  2.5) 
with  extensive  catarrhal  symptoms  ;  sputum  contained  tubercle 
bacilli ;  high  fever ;  continuous  decrease  in  weight,  so  that 
clinically  no  doubt  was  entertained  that  the  disease  would 
take  a  rapid  and  unfavourable  course.  The  result  of  the 
reaction  on  May  9,  1907,  was  strongly  positive  (strong  con- 
junctivitis   with    purulent    secretion,    reaching    a    maximum 


DIAGNOSIS    OF    TUBEKCULOSIS  45 

after  thirtj^-six  hours,  and  then  regressiiif^;).  According  to  my 
explanations  concerning  the  prognostic  significance  of  the 
positive  reaction,  there  was  a  possibihty  in  this  case  that 
the  process  might  still  be  arrested  and  perhaps  take  a  more 
benign  course.  And  indeed  the  fever  suddenly  ceased,  and 
the  subjective  condition  became  so  favourable  that  the  patient 
was  able  to  remain  in  the  open.  Soon  the  expectoration 
ceased  altogether,  the  patient's  weight  increased  10  lb.  in  the 
course  of  four  weeks,  and  she  was  dismissed  with  diminished 
resonance  over  the  lower  lobes,  and  weakened  breath-sounds 
with  slight  rattling. 

Case  8. — In  one  female  patient  (Lindeinann,  1)  we  found 
tuberculosis  of  the  second  to  the  third  stage.  Three  weeks 
before  death  there  was  a  strong  positive  response  to  the  con- 
junctival, a  negative  response  to  the  cutaneous,  reaction. 
This  led  us  to  expect  that  the  disease  would  not  progress 
much,  and  that  death  was  not  yet  near ;  the  further  course 
of  the  disease  was  in  accordance  with  this  assumption.  The 
fever  decreased,  remained  insignificant,  and  sometimes  was 
entirely  absent.  The  weight  of  the  patient  did  not  decrease  ; 
she  sat  up  for  hours  when  she  felt  well.  Suddenly  she  got 
a  strong  attack  of  haemoptysis,  and  died  in  the  course  of 
a  few  days. 

We  do  not  believe  that  this  case  is  in  contradiction  with 
our  theories.  The  reactive  capacit}^  indicates  the  possibility 
of  a  favourable  course,  based  on  the  capacity  of  the  body 
to  prevent  the  extension  of  the  symptoms  of  the  disease. 
Haemoptysis  is  accidental,  and,  although  it  cannot  be  com- 
pared with  a  traumatic  affection,  it  yet  represents  a  coin- 
cidence not  directly  connected  with  the  extension  of  the 
symptoms  of  tuberculosis. 

Following  on  these  cases  we  will  mention  the  exceptions, 
all  of  which  turn  on  the  point  that,  despite  a  positive  reaction, 
the  course  of  the  disease  was  not  so  favourable  as  might  have 
been  expected  after  the  favourable  experiences  in  the  other 
cases. 

Case  4. — A  female  patient  (Madame  Schulz,  Pavilion  1), 
who  gave  strong  reactions,  but  who  nevertheless  showed 
severe  clinical  symptoms  with  high  remittent  fever.  For  six 
to  eight  w'eeks  the  disease  has  not  realh^  become  worse,  yet 
the  affection  in  the  lungs  increased.  At  the  end  of  the 
observation  the  same  hyper-sensibility  existed.  The  reaction, 
when  repeated,  was  again  a  strong  one. 


46  THE  OPHTHALMIC  AND  CUTANEOUS 

Case  5. — Another  patient  (Schroder,  Pavihon  17)  showed, 
post  mortem,  extensive  King  symptoms  and  fresh  dissemina- 
tions over  the  inferior  lobes  despite  strong  reaction. 

Such  exceptions  are  very  rare.  Stadehnann,  in  writing 
on  the  subject,  says  :  "  There  certainly  are  exceptions,  but 
they  seem  to  be  extremely  rare." 

They  occur  in  cases  in  which  the  reactive  capacity  of  the 
body  could  not  win  the  battle  against  the  other  factors  in 
operation.  On  the  other  hand,  cases  showing  a  defective 
reactive  capacity  hardly  produce  any  exceptions  as  to  their 
unfavourable  course.  Of  those  clinically  regarded  as  the 
first  stage  one  has  died  (Kohler,  Pavilion  17)  and  yost  mortem 
it  was  seen  that  the  changes  were  actually  those  of  the  third 
stage,  and  that  the  reaction  had  given  a  better  idea  of  the 
disease  than  the  painstaking  clinical  investigations.  Of  those 
in  the  second  stage  who  did  not  produce  a  reaction  one  died, 
whilst  four  passed  on  into  the  third  stage  and  are  expected 
to  die  within  a  short  time.  Of  18  patients  in  the  third  stage 
15  did  not  give  a  cutaneous  reaction  and  13  did  not  give  a 
conjunctival,  and  out  of  these  14  have  already  died,  after  six 
weeks. 

Also,  according  to  the  observations  of  Pirquet  {Wiener 
Mm.  Wochenschr.,  1907,  No.  38),  the  reactive  capacity  in 
children  decreases  shortly  before  death.  Out  of  five  tests  only 
one  reacted  positively  six  to  nine  days  before  death.  Out  of 
24  cases  investigated  during  the  last  ten  days  of  life  13 
reacted  negatively  and  only  11  positively.  The  decrease  can 
also  be  measured  quantitatively. 


Days  ante  mortevi 

Dilutions 

Cutaneous  reaction 

14 

11 

6 

1  :  1000 
1  :     100 

1  :       61 

+ 

THE     BEHAVIOUR     OF     THE     REACTION     IN     HEALTHY 
INDIVIDUALS. 

Now  that  we  have  dealt  with  the  course  of  the  specific 
reaction  in  individuals  in  whom  distinct  tuberculous  changes 
have  taken  place,  that  is  to  say,  in  those  individuals  in  whom 
it  would  be  easiest  to  obtain  a  picture  of  the  course  of  the 
specific  reaction,  I  think  it  desirable  to  follow  the  course  of 
the  reaction  in  healthy  individuals.     By  the  term  "  healthy  " 


DIAGNOSIS    OF    TUBERCULOSIS  47 

individuals  we  mean  people  who  are  being  treated  in  hos- 
pitals for  other  diseases,  and  who,  according  to  the  most 
painstakmg  clinical  investigations,  do  not  give  us  any  reason 
to  suspect  the  presence  of  tuberculous  changes.  It  could, 
of  course,  not  be  doubted  that  amongst  these  so-called 
"  healthy  "  individuals  there  were  a  few  in  whom  tuberculous 
changes  had  taken  place,  and  a  great  number  with  latent 
and  healed  up  or  inactive  tuberculous  centres.  We  think 
it  desirable  that  such  healthy  individuals  should  also  be 
examined  in  order  that  their  behaviour  with  regard  to  the 
reaction  should  become  known  ;  suspected  individuals  always 
present  difficult  conditions,  since  amongst  them  we  find  partly 
tubercular  patients  in  the  beginning  of  the  first  stage  of  the 
disease,  and  partly  healthy  individuals.  It  will  therefore 
become  much  easier  to  judge  the  results  when  we  shall  be 
able  to  point  to  distinct  differences  between  non-tuberculous 
and  tuberculous  people  in  their  behaviour  with  regard  to 
the  reactions. 

Our  material  amounts  to  192  cases,  exactly  half  of  which, 
by  cutaneous  reaction,  gave  positive  results,  whilst  the  other 
half  gave  negative  reactions.  Of  the  positive  cases  28 
exhibited  traces,  59  the  first  degree  of  reaction,  8  the  second, 
and  1  the  third  degree.  In  26  persons  there  was  late  reaction. 
As  we  shall  see  further  on,  special  significance  attaches  to 
the  late  reaction,  and  one  might  even  be  justified  in  not 
regarding  the  latter  as  a  positive  reaction. 

But  even  after  this  deduction  70  positive  cutaneous 
reactions  remain  against  only  35  positive  conjunctival 
reactions,  of  which  latter  14  gave  traces,  17  the  first  degree 
and  4  the  second  degree  of  reaction.  From  the  number  of 
positive  conjunctival  reactions  one  may  deduct  two  late 
reactions. 

The  Difference  in  the  Besiilts  of  both  Beaciions  in  CUnicalhj 
Unsuspected  Individuals. — In  tuberculous  patients  hardly  any 
essential  differences  could  be  found  between  the  results  of  the 
cutaneous  and  the  conjunctival  reactions,  the  one  reaction  being 
not  even  stronger  than  the  other.  We  here  find  for  the  first 
time  a  much  greater  responsiveness  in  the  cutaneous  reaction, 
that  is  to  say,  a  responsiveness  which  is  to  its  disadvantage, 
because  we  have  to  do  with  clinically  healthy  persons.  In 
thirty-two  cases  the  cutaneous  reaction  was  stronger  than  the 
conjunctival  reaction,  whilst  in  only  three  cases  the  opposite 
was  the  case.     This  frequent  response  in  cutaneous  reactions 


48  THE  OPHTHALMIC  AND  CUTANEOUS 

in  apparently  healthy  individuals  has  caused  even  its  dis- 
coverer to  regard  the  reaction  as  of  diagnostic  use  in  the  case 
of  children  only/  and  for  this  reason  Citron  (Berl.  nied.  Ges., 
July  '24,  1907)  simply  regards  the  cutaneous  reaction  as  useless 
("  all  persons  show  this  [cutaneous]  reaction,  except  some 
cachectic  individuals"),  whilst  the  majority  of  French  writers, 
who  have  worked  with  the  ophthalmic  reactions,  have  hardly 
taken  the  trouble  to  carry  out  any  investigations  with  the 
cutaneous  reaction.- 

AVe  must  here  state  that  the  possibility  of  coincidence  in 
the  material  or  of  mistakes  is  excluded,  the  more  so  since 
the  results  arrived  at  by  other  authors  point  to  the  same 
thing,  and  even  show  a  tendency  to  more  clearly  indicate 
the  differences  (Frankel,  for  instance,  only  obtains  5  per 
cent,  reactions  ;  Eppenstein  at  most  5  per  cent,  with  the 
conjunctival  method).  Bandler  and  Kreibich  {Deutsche  med. 
Wochenschr.,  1907,  No.  40)  obtained  88  cutaneous  reactions 
out  of  02  healthy  individuals,  &c. 

Probable  Explanation. — It  is  not  a  very  easy  matter  to 
explain  these  differences  in  the  results,  but  from  a  clinical 
point  of  view  this  divergence  of  both  methods  is  of  very  happy 
auoury.  The  difference  between  the  reactions  is  as  follows  : 
The  cutaneous  reaction  indicates  the  presence  in  the  body 
of  an  inactive  and  encapsuled  tubercular  centre,  which  does 
not  manifest  clinical  symptoms,  and  which  may  not  even  be 
capable  of  again  becoming  active ;  in  other  words,  it  mdicates 
that  at  one  time  or  another  the  body  has  in  some  way  come 
in  contact  with  tubercle  bacilli.  The  ophthalmic  reaction, 
on  the  other  hand,  merely  indicates  that  active  or  semi-active 


'  Burnet  {Soc.  de  Biol..,  1907)  has  observed  the  course  of  the  reaction 
in  himself  and  his  colleagues,  that  is  to  say,  in  clinically  healthy  in- 
dividuals ;  it  seems  to  have  been  a  reaction  in  the  sense  of  our  late 
reaction. 

-  It  is  interesting  to  note  that  Schenck  and  Seiffert  had  tlie  same  result 
witli  regard  to  the  conjunctival  reaction  as  we  have  had  with  the  cutaneous, 
by  repeating  the  conjunctival  reaction  three  times  in  clinically  healthy 
persons  (positive  reaction  in  50  per  cent.).  This  supports  our  conclusions 
to  an  extraordinary  extent  (see  the  theoretical  part). 

Lenhartz  in  forty  healthy  people  found  both  reactions  to  be  negative 
(four  had  not  been  treated  with  the  conjunctival  method)  ;  in  all  other  cases 
fovir  gave  positive  reactions. 

Schubert  always  obtained  negative  reactions  in  healthy  individuals. 

Mainini  (Miinch.  med.  Wochenschr.,  1907,  No.  52)  is  the  first  to  follow 
our  idea,  and  to  apply  both  reactions  in  each  case. 


DIAGNOSIS    OF   TUBEKCULOSIS  49 

tubercular  centres  are  present.  These  conclusions,  apart  from 
clinical  observations,  can  be  arrived  at  by  studying  the  figures. 
Now  it  is  much  more  probable  that  out  of  192  apparently 
healthy  people,  35  (=  about  one-sixth)  would  possess  imper- 
fectly cured  tubercular  centres  than  96.'  Further  confirma- 
tion of  the  actual  presence  of  tubercular  centres  in  the  body 
is  obtained  when  the  tuberculin  reaction  (see  this  chapter) 
coincides  with  the  other. 

Greater  Clinical  Significance  of  the  Conjunctival  Reaction. 
— It  is  not  to  be  doubted,  therefore,  that  the  conjunctival 
reaction  certainly  can  claim  and  does  possess  the  greater 
clinical  significance.  Clinicians  do  not  interest  themselves 
in  activities  of  the  past ;  they  wish  to  know  whether  in  any 
particular  body  they  are  investigating  there  are  still  tuber- 
cular centres  claiming  their  attention  and  care.  They  feel 
comparatively  little  for  inactive,  encapsuled,  healed  up, 
expired,  harmless  processes.  I  do  not  mean  to  say  that  the 
cutaneous  reaction  should  be  neglected  ;  one  may  not  maintain 
that  it  is  without  any  clinical  interest  whether  in  any  par- 
ticular case  a  tubercular  process  has  healed.  In  fact,  in  the 
investigation  of  a  great  number,  and  for  purely  scientific 
purposes,  such  observations  are  of  the  utmost  importance. 
The  similarity  in  results  of  both  these  reactions  make  the 
cutaneous  reaction  a  very  miportant  means  of  control,  since 
technical  mistakes  do  sometimes  occur  ;  the  more  so  since 
the  non-appearance  of  the  reaction  is  indicative  of  important 
prognostic  conclusions,  which  might  be  based  on  a  mistake 
if  the  conjunctival  reaction  alone  were  relied  upon.  It  is 
especially  important  to  ascertain  that  the  cutaneous  reaction 
only  very  rarely  fails,  but  that  if  it  does  fail  in  tuberculosis, 
it  fails  together  with  the  conjunctival  reaction  ;  and  it  is  only 
when  we  find  that  both  reactions  fail  to  respond  in  one  and 
the  same  case  that  we  may  safely  draw  the  so  very  important 
prognostic  conclusion. 

The  cause  of  the  difference  in  these  two  methods  probably 
lies — as  has  been  pointed  out  before — in  the  different  absorp- 

'  We  cannot  possibly  enter  into  a  discussion  with  those  authors  who 
never,  or  hardly  ever,  obtain  conjunctival  reactions  in  clinically  health}' 
individuals.  Even  if  we  assume  that  the  authors  in  question  have  greater 
capability  than  ourselves  in  instituting  clinical  investigations,  yet  autopsy 
and  subcutaneous  tuberculin  injections  clearly  show  that  tuberculous 
centres  may  exist  in  clinically  healthy  individuals  ;  it  is  at  least  very 
probable  that  our  observations  are  the  more  correct  ones. 

4 


50  THE  OPHTHALMIC  AND  CUTANEOUS 

tive  capacity  of  the  parts  of  the  body  in  which  the  reaction  is 
performed.  The  skin,  having  but  shght  power  of  absorption 
compared  to  the  conjunctiva,  retains  the  concentrated  tuber- 
cuHn  until  the  ceUs — which  for  a  long  time  had  ceased  to  be 
influenced  by  tuberculin  by  reason  of  the  tubercular  centre 
being  latent — regain  their  reactive  capacity  through  tlie  con- 
tinuous stimulation.^  The  quickly  absorbing  conjunctiva, 
however,  remains  for  too  short  a  time  in  contact  with  the 
tuberculin,  the  anatomical  conditions  aiding  the  expulsion  of 
the  instilled  fluid. 

It  is  evident  from  our  explanations  concerning  the  reasons 
inducing  earlier  authors  not  to  attach  any  clinical  value  to 
the  cutaneous  reaction  that  the  latter  must  have  found  an 
even  larger  percentage  of  positive  reactions  than  ourselves. 
And,  in  fact,  von  Pirquet  found  that  only  new-born  infants  and 
young  children  do  not  react,  and  that  with  increasing  age 
the  percentage  of  positive  reactions  increases  until,  with  very 
few  exceptions,  all  adults  respond  positively,  except  in  very 
advanced  cases.  It  is  difficult  to  explam  why  we  should 
have  obtained  reactions  in  fewer  cases.  It  may  be  because 
of  our  technique  ;  also  we  do  not  regard  as  positive — contrary 
to  Pirquet — the  very  slight  traces  of  a  reaction,  but  only  clear 
and  distinct  reactions,  the  only  course  to  pursue  for  practical 
purposes  and  in  experimenting  on  a  large  scale.  The  autopsies 
prove  most  decidedly  that  we  were  right  in  our  conclusion 
(which  in  the  first  instance  had  been  based  on  figures  only) 
with  regard  to  the  clinical  superiority  of  the  conjunctival 
reaction,  and  that  the  cutaneous  reaction  is  so  very  sensitive 
that  it  brings  to  light  the  presence  of  inactive  tubercular 
centres  in  the  body.  I  append  a  table  compiled  by  Stadel- 
mann,  which  shows  this  very  clearly. 

The  Autopsies  sitpport  the  Value  of  the  Cutaneous  Reaction 
for  Discovering  Latent  Tubercular  Centres. — In  five  cases  in 
which  no  response  was  obtained,  either  in  the  cutaneous  or 
the  conjunctival  reaction,  no  trace  of  tuberculous  changes 
could  be  found  on.  post-mortem  examination.  The  same  held 
ofood  for  a  sixth  case  which  had  shown  traces  in  cutaneous 
reaction,  whilst  out  of  eight  cases  in  which  a  response  was 
obtained  in  the  cutaneous,  but  not  in  the  conjunctival  re- 
action, six  possessed  old  encapsuled  and  healed  up  tubercular 


'  In  order  to  avoid  being  misunderstood,  we  emphatically  refer  to  the 
Theoretical  Part. 


DIAGNOSIS    OF   TUBERCULOSIS 


51 


centres  in  different  parts  of  the  body,  whilst  in  only  one 
case  there  was  visible  tuberculosis ;  in  one  case  only — that 
of  a  cachectic  individual — recent  tuberculosis  was  found  in 
the  apex.  (In  this  case,  according  to  Stadelmann,  an  experi- 
mental mistake  has  been  made.  I  am  inclined  to  leave  the 
question  open.) 

Considering  the  enormous  number  oi  post-mortem  examina- 
tions carried  out  at  the  Friedrichshain  Hospital,  the  number 
of  cases  above  mentioned  is  not  very  great.  This,  however, 
is  due  to  the  fact  that  we  have  not  taken  into  considera- 
tion any  post  mortems  on  advanced  tubercular  patients,  because 
little  interest  is  attached  to  them  ;  a  great  number  of  people 
come  into  the  hospital  in  a  dying  condition,  the  reactions 
not  being  applied,  since  no  definite  conclusions  could  be 
drawn  from  their  behaviour. 


POST-MORTEM    RESULTS. 

We  will  give  the  post-mortem  results  in  the  form  of  a 
table.  The  reason  for  the  small  number  of  investigations 
has  been  discussed  above.  Future  investigation  wall  have 
to  be  carried  out,  especiall}^  along  the  lines  of  post-mortem 
examinations,  because  the  time  elapsed  since  the  discovery 
of  the  reactions  has  not  been  sufficiently  long  for  the  collec- 
tion of  a  great  deal  of  post-mortem  material. 

The  following  points  have  to  be  taken  into  account  for 
the  scientific  appreciation  of  the  post-mortem  results.  That 
there  are  no  apparent  tuberculous  changes  is  no  proof  of 
the  absence  of  tuberculosis.  This  has  been  made  clear  by 
Orth  many  years  ago.  But  even  if  microscopical  alterations 
cannot  be  found,  experiments  on  animals  may  often  prove 
the  presence  of  tuberculosis  (see  the  elaborate  treatment 
of  the  subject  by  Kabinowitsch,  Berl.  klin.  Wochenschr.,  1907). 
For  all  highly  scientific  purposes  this  course  must  be  followed. 
Oi\\ev  post-mortem  results  confirm  our  statements  : — 

VON  PiRQUET  [Wien.  klin.  Wochenschr.,  1907,  No.  .38)  in  Children. 


Author 

Cases 

Cutaneous 
reaction 

Post-mortem  examination 

von  Pirquet 

Comby 

( Fresse  vied. ,  Aug.  10, 

1907.) 

31 

)         52 

4 
)           6 

1   +   1        + 

Tuberculous  changes,  at  auy 
rate  caseated  glands. 

No  tuberculosis. 
Tuberculous  changes. 
No  tuberculosis. 

There   was    only    one    case    with    reaction    without    microscopically    visible 
tuberculosis. 


D    -5 


E 
o 

c 
d 

i 

o 

No  tuberculous  processes  of  any  kind. 

Remarks 

z; 
o 

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1 
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1 
\-         1    1    1    1    1    1    1 

DinK"0»is 

Ulc.  endoc.  . . 

Myocarditis 

Leucocyth;emia 

Pericarditis.. 

Hepatic  cirrh. 

Sclerosis  of  arteries,  cholelith.  . . 

Syphilis  III.,  aortic  insufficiency 

1 

is 

(1)  Matthes  . . 

(2)  Lciw 

(3)  Burgh.     .. 

(4)  Lieb 

(5)  Fuchs      .. 

(6)  Wiese      .. 

(7)  Hiichstn. 

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DIAGNOSIS    OF   TUBERCULOSIS  58 

Von  Pirquet  (Wien.  klin.  Wochenschr.,  1907,  No.  38):  In 
patients  found  tuberculous  on  post-mortem  examination,  the 
reaction  had  been  partly  positive,  partly  positive  when  re- 
peated, partly  negative  ;  out  of  13  :  6,  3,  4,  respectively  ;  in 
totally  calcified  tubercular  centres  the  reactive  capacity  in 
one  case  disappeared  without  any  explanation  being  afforded 
by  the  autopsy. 

Late  and  Lasting  Beaction  the  Reaction  of  Healthy  Indi- 
viduals.— As  we  have  already  noticed,  a  late  reaction  only 
occurs  extremely  rarely  in  tuberculous  individuals.  We  have 
already  dealt  with  the  type  of  the  reaction  in  the  case  of 
actual  tuberculosis,  and  the  curve  figures  further  on  clearly 
show  the  rapid  increase  and  decrease  of  the  reaction.  Judg- 
ing by  the  great  number  of  cases  with  positive  reaction  in 
healthy  individuals,  it  would  seem  as  if  the  late  reaction  is  the 
reaction  of  non-tubercuious  individuals,  or  perhaps  of  people 
with  healed  up  tuberculosis.  A^ery  painstaking  clinical  obser- 
vations and  post-mortem  results  support  this  view.  Great 
significance  is  attached  to  the  late  reactions,  since  they  will 
enable  us  to  understand  the  hypersensibility  reactions.  We 
will  return  to  this  point  in  the  Theoretical  Part. 

The  Conjunctival  Reaction  in  Typhoid  Patients.  —  After 
having  dealt  with  the  reaction  in  healthy  individuals  we  will 
now  refer  to  those  observations  which  show  that  in  the  case 
of  typhoid  patients  and  convalescent  persons  a  special  reactive 
capacity  exists  with  regard  to  the  conjunctival  instillation  of 
tuberculin.  Cohn,  going  by  his  own  observations  as  well  as 
by  the  literature,  calculates  about  80  per  cent.  Although, 
of  course,  the  calculation  of  percentages  on  so  small  a  number 
of  observations  is  not  very  reliable,  yet  this  number  is  very 
remarkable,  especially  since  Kraus,  Lusenberger  and  Kuss 
{Wien.  klin.  Wochenschr.,  1907,  Xo.  45)  found  out  of  twelve 
cases  of  typhoid  eleven  in  which  a  conjunctival  reaction  by 
tuberculin  w^as  obtained. 

A.  Frankel  suggested  that  individuals  saturated  with  bac- 
terial toxins  would  exhibit  some  sensibility  with  regard  to 
every  form  of  bacterial  albumin,  which  at  the  same  time 
would  go  to  prove  the  often  doubted  specific  nature  of  the 
albuminous  substances  constituting  the  separate  bacteria. 
Kraus  arrives  at  similar  conclusions. 

Testing  the  problem  on  our  own  material,  apart  from  any 
theoretical  reasoning,  we  come  to  entirely  different  conclu- 
sions.    In    eight   typhoid  patients  the  reaction  proved  to  be 


54  THE  OPHTHALMIC  AND  CUTANEOUS 

absolutely  negative,  and  I  regard  the  fact  that  in  most  cases 
the  cutaneous  reaction,  which  had  a  tendency  to  turn  out 
positive,  has  remained  negative  as  a  control  to  the  correctness 
of  these  observations. 

Wassermann  and  also  Fritz  Levy  inform  me  that  in 
typhoid  patients  they  did  not  obtain  a  reaction,  whereas  in 
convalescent  persons  it  occurred  frequently.  We  have  not 
been  able  to  obtain  positive  reactions  either  in  typhoid  con- 
valescence or  in  articular  rheumatism. 

THE    BEHAVIOUR    OF    THE    REACTION    IN    DOUBTFUL    CASES. 

We  now  come  to  the  most  important,  and  at  the  same 
time  the  most  difficult,  part  of  our  explanation,  the  behaviour 
of  the  reaction  in  doubtful  cases,  of  which  only  twenty  have 
been  under  protracted  observation.  All  these  cases  were 
suspected  on  clinical  grounds  of  being  in  the  very  early  stages 
of  pulmonary  tuberculosis,  but  no  certainty  was  obtained. 
Sixteen  showed  positive  cutaneous  reactions,  twelve  positive 
conjunctival  reactions.  Just  as  is  the  case  in  healthy  indi- 
viduals, positive  results  are  more  frequently  obtained  with 
the  cutaneous  than  with  the  conjunctival  reaction,  but  the  dif- 
ferences here  are  not  so  great.  To  begin  with,  we  must  assume 
that  amongst  these  doubtful  cases  there  were  actually  some 
who  were  in  the  early  stages  of  tuberculosis  and  others  who 
were  non-tuberculous.  Therefore,  in  diagnosing  the  reaction, 
we  will  base  our  judgment  on  the  types  of  reaction  in  tuber- 
culous individuals  of  the  first  stages  and  in  healthy  persons. 
After  what  has  been  explained  before  we  will  disregard  the 
late  reactions  for  the  moment  and  regard  the  latter  as  the 
reactions  of  healthy  individuals  ;  this  reduces  the  differences 
between  the  two  methods  to  two.  Those  cases  in  which  both 
reactions  have  been  obtained  we  will  regard,  duly  considermg 
the  possibility  of  errors,  as  being  in  the  beginning  of  the  first 
stage  of  pulmonary  tuberculosis. 

The  classification  of  jthe  reactions  does  not  present  any 
further  difficulties.  Of  the  cutaneous  reactions  six  showed 
traces,  seven  the  first  degree,  three  the  second  degree ;  in  the 
conjunctival  method  seven  showed  traces,  three  the  first 
degree,  two  the  second  degree.  In  two  cases  the  cutaneous 
reaction  was  stronger  than  the  conjunctival. 

The  result  of  the  reaction  in  doubtful  cases  is  the  touch- 
stone  for  its   diagnostic   value.      Above  we  have   laid  stress 


DIAGNOSIS    OF   TUBERCULOSIS  55 

on  the  diagnostic  significance,  but  this  is  not  a  matter  of 
importance  m  cases  which  present  hut  little  difficulty  to  the 
experienced  chnician.  As  far  as  cases  of  manifest  tuberculosis 
are  concerned,  the  greatest  advantage  of  the  reaction  lies 
in  its  prognostic  value.  This  attribute  of  the  reaction  lias 
been  curiously  overlooked  by  all  French  writers  who  have 
introduced  the  reaction  into  clinics  according  to  their  lights, 
although  from  my  very  first  communication  to  the  Bed.  med. 
Gesellsch.,  May  15,  1907,  I  have  specially  emphasized  this 
point. 

Difficulties  encountered  i)i  the  Use  of  the  Reaction  in 
Doubtful  Cases. — In  doubtful  cases  the  appreciation  of  the 
diagnostic  value  of  the  reaction  is  much  more  difficult  than 
in  the  manifestly  tuberculous  cases.  I  cannot  possibly  under- 
stand how  most  writers  on  the  subject  can  have  come  to  a 
conclusion  in  the  course  of  a  few  weeks.  Despite  the  much 
longer  time  I  have  spent  in  investigating  this  subject,  I  do 
not  regard  our  observation  as  sufficient,  although  during  the 
six  months  of  our  actual  investigation  we  found  a  few  cases 
which  to  some  extent  corroborated  our  views.  Also  in  these 
cases  we  had  to  apply  the  usual  diagnostic  methods,  and, 
when  necessary,  to  test  the  identity  of  the  result  of  the  sub- 
cutaneous tuberculin  reaction  with  that  of  the  cutaneous  and 
conjunctival  reactions. 

The  fact  cannot  be  denied  that  the  discovery  of  a  substi- 
tute for  the  tuberculin  method — the  danger  of  which  has  only 
recently  been  confirmed  by  a  new  example — would  in  itself 
constitute  a  great  attainment,  even  if  the  new  method  had 
no  other  advantages  ;  and  indeed,  our  observations,  chronicled 
in  the  following  table  of  Stadelmann,  and  which  coincide 
with  the  observations  of  Levy  and  others,  show  that  a  far 
reaching  correspondence  certainly  exists. 

Explanation  of  the  Tables. — As  is  evident  froui  the  tables, 
the  subcutaneous  tuberculin  injection  was  commenced  with 
O'OOl  gramme  of  tuberculin,  which  was  increased  to  0  007 
gramme  and  even  0"008  gramme  if  the  reaction  did  not 
appear.  The  last-mentioned  dose  is  too  great,  so  that  few, 
including  ourselves,  attach  any  diagnostic  importance  to  it. 

The  positive  cutaneous-conjunctival  reactions  have  in  all 
cases  corresponded  with  the  control  tuberculin  injections,  a  fact 
with  which  most  writers  have  agreed.  The  value  of  this  cor- 
respondence lies  in  the  fact  that  if  further  investigations  con- 
firm this  behaviour,  the  cutaneous  and  conjunctival  reactions 


56  DIAGNOSIS    OF    TUBERCULOSIS 

will,  for  all  practical  purposes,  replace  the  subcutaneous  in- 
jection of  tuberculin.  However  little  I  may  be  in  favour  of 
the  subcutaneous  application  of  tuberculin,  I  must  yet  enjoin 
clmicians  to  test  the  concordance  of  the  two  reactions  most 
thoroughly  in  order  that  we  may  be  able,  as  soon  as  possible, 
to  replace  the  subcutaneous  tuherculin  reaction  by  tJie  local 
reaction.  We  must  mention  that  the  table  shows  a  number 
of  cases,  clinically  not  suspected,  in  which  a  positive  local 
reaction  was  obtained,  and  in  which  the  subsequent  tuberculin 
reaction  also  gave  a  positive  result.  This,  therefore,  according 
to  our  present  knowledge,  clearly  indicated  the  existence  of 
tuberculosis.  It  is  of  interest  to  notice  that  out  of  the  four 
clinically  not  suspected  cases  in  which  a  cutaneous  and  a 
conjunctival  reaction  had  been  obtained,  two  reacted  on  a 
very  minute  dose  (0"001  gramme). 

Examples. — We  will  adduce  a  few  histories  of  diseases 
on  account  of  the  great  interest  attached  to  them.  Leipold 
(Pav.  6a)  had  sanguineous  pleuritic  exudation,  expectoration, 
coughing,  and  sputum  resembling  raspberry  jelly  containing 
uninuclear  cells.  Clinically  it  was  thought  that  tumour  of 
the  lung  existed  (on  account  of  the  appearance  of  the  sputum, 
and  because  of  its  distinctly  hsemorrhagic  character).  The 
conjunctival  reaction  was  positive,  and  later  on  tubercle  bacilli 
appeared  in  the  sputum.  The  tubercuHn  reaction  was  also 
applied,  producing  38*2^  C.  by  a  reaction  on  0-003  c.cm.  of 
tuberculin. 

Another  case  (Kirste,  Pav.  17)  is  worth  mentioning  in 
which  tuberculosis  was  assumed  to  exist  on  account  of  the 
general  condition  constituting  an  etiological  basis  for  a 
pleuritic  exudation  (his  father  having  died  of  pulmonary 
tuberculosis;.  The  result  of  both  local  reactions  was  nega- 
tive, which  is  remarkable  in  view  of  the  fact  that  Levy  in 
his  material,  which  contained  a  good  many  cases  of  pleuritic 
exudation,  has  always  observed  strongly  marked  reactions 
in  such  cases.  Nor  was  the  suspicion  as  to  the  presence  of 
tuberculosis  supported  by  the  clinical  course  of  the  disease  ; 
the  exudation  was  soon  absorbed,  the  fever  left  soon  after, 
and  permanently,  the  sputum  was  examined  several  times 
and  was  never  found  to  contain  any  tubercle  bacilli,  and 
finally  it  disappeared  altogether. 

Tubercuhn  injection  of  O'OOl  gave  a  temperature  of 
37'4^  C,  and  it  was  only  at  the  injection  of  0"007  c.cm.  (!) 
that   it  rose  to  38'4''  C.     GeneraL  symptoms  were  observed. 


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CG 

After  the  tuberculin  injection  dis- 
tinct hoarse  breathing  and  crepi- 
tation over  the  left  apex  ;  no 
sputum.  The  patient  remains 
clinically  suspected. 

No  sputum.  General  state  of  health 
good  ;  but  declined  in  sanatorium 
(slight  catarrh,  apex  of  right  side). 

After  repeated  seai-ch  tubercle  ba- 
cilli found  in  sputum. 

Disturbed  general  health  ;  fever 
remained  from  24—48  hours, 
then  decreased.  An  old  tuber- 
culous cavity  found. 

Hereditary  connections  ;  no  spu- 
tum. 

Fever   nearly   gone  ;    no   tubercle 

bacilli  in  the  sputum. 
No  bacilli  found  in  sputum. 

After  the  tuberculin  injection  slight 
increase  of  fever  during  four  days; 
no  sputum  ;  uo  symptoms  of  pul- 
monary infiltration. 

5 

i 

3 
O 

1 
3 
EH 

Only  reacts  on  0*007,*  show 
ing  fever  up  to  39*2°  C. 

On   0-001  no   reaction,  on 
0  003  fever  up  to  38 -2"  C. 

On  0*001  no  reaction,  on 
0-003  fever  up  to  38-2°  C. 

On  0001  after  six  hours 
fever  up  to  38*4°  C. 

On  0-001  no  reaction,   on 
0-003  fever  up  to  39-5°  C. 

On  O'OOl  no  reaction,  on 
0-003  fever  up  to  38-6°  C. 

Only  on  0-007  tuberculin 
fever  up  to  38-0°  C. 

On  0  001  fever  up  to  390°  C. 

z; 
o 

o 

Ed 

03 

"3 
> 

o 

3 

'5° 

o 

C3  - 

Trace 
Trace  + 

repeated  trace 

+  ,  trace,  trace 

trace 

s 

§ 

c 
5 

=) 

Q 

CI 

Trace 

Late  reaction 

on  fourth 

day  + 

-f  i./n., 

-f-  trace 

Trace  -f,  +,  +, 
repeated  -f 
Trace,  trace, 
trace,  trace 

o 

5 

Catarrh,  apicis.      Sus- 
pected of  tuberculosis 

Catarrh,   apicis.     Sus- 
pected of  tuberculosis 

Pleurit.  exud.  Slightly 
suspected 

Pleurit.  exud.  Sus- 
pected of  tuberculosis 

Suspected  of  pulmon- 
ary tuberculosis 

Hscmoptysis  ;  infiltra- 
tration  of  the  left  apex 
Tuberc.  apic.  sinistr. . . 

Pleurit.   peritonit.   tu- 
berc. 

2 
5 

(8)  Gost.  (Pav.  17)  . . 

(9)  Post.  (Pav.  17)    . . 

(10)  Leip.  (Pav.  Ga)    . . 
(2)  Brenu.  (Pav.  1)  . . 

(G)  Griitzm.  (Pav.  Ga) 

(5)  Chask.  (Pav.  Ga).. 

(13)  Schoss.  (Pav.  Ga) 

(14)  Kriig.   (Pav.  Ga)  . . 

60  THE  OPHTHALMIC  AND  CUTANEOUS 

Only    three    days    elapsed    between    the    apphcation    of    each 
injection. 

Nother  (Pav.  17)  had  a  strong  pleural  effusion  on  the 
right  side.  After  puncture  the  fever  disappeared,  the  effusion 
was  reabsorbed,  and  the  patient  felt  quite  v/ell.  Clinically 
no  suspicion  of  tuberculosis  was  entertained.  The  cutaneous 
and  conjunctival  reactions  were  very  strong  : — 

1st    i   2nd       3rd       4th    ,   5th  days 


Cutaneous  +  +  decreasing 

Conjunctival     ,     +     |     +  +  +      decreasing 

The  diagnosis  of  pleuritis  tuberculosa  was  supported  by 
the  result  of  a  subcutaneous  tuberculin  injection  0"003  ; 
reaction  up  to  38'6'  C. 

In  the  Theoretical  Part  I  will  deal  with  the  diagnostic 
objections  against  the  repetition  of  control  tuberculin  injec- 
tions. Since  we  must  start  from  that  which  may  be  regarded 
as  proven,  I  will  not  emphasize  this  point  here,  leaving  it 
to  everyone  to  draw  his  own  conclusions  from  the  results  of 
the  tuberculin  reactions  when  a  high  dose  is  applied.  It 
would,  however,  appear  to  me  that  the  local  reactions  have 
already  been  shown  to  possess  distinct  advantages  over  the 
subcutaneous  injection  as  far  as  their  clinical  diagnostic 
significance  is  concerned. 

I  will  leave  it  to  the  logical  and  unprejudiced  clinician, 
Stadelmann,  to  pronounce  a  synthetic  judgment  on  the  value 
of  the  reaction.  He  expresses  himself  in  the  followmg  words  : 
"  The  justification  of  a  suspicion  of  tuberculosis  by  the  re- 
action can  only,  of  course,  in  the  first  instance  be  found  in 
the  course  of  the  disease  and  in  clinical  observation,  which 
naturally  has  to  extend  over  a  fairly  long  period,  so  that  a 
final  opinion  cannot  be  given  easily  and  within  a  very  short 
time.  In  a  number  of  cases,  however,  we  have  actually 
succeeded,  and  I  may  express  satisfaction  at  the  fact  that 
our  critical  and  objective  judgment  in  all  cases  corresponded 
with  the  result  of  the  reaction." 

The  Experiences  of  other  Authors  icith  the  Reactions. — 
Eppenstein  has  investigated  seventy-six  doubtful  cases  and  has 
obtained  positive  reactions  in  about  40  per  cent.  An  absolute 
figure  cannot  be  given  since  he  does  not  distinguish  between 
those  who  reacted  at  once  and  those  who  reacted  only  after 
a  repeated  application.  It  is  only  worth  while  to  mention  six 
cases  of  chronic  exudative  pleuritis  with  positive  reactions. 


DIAGNOSIS    OF   TUBERCULOSIS 


61 


Lenhartz,  in  sixty-three  doubtful  cases,  obtained  twenty- 
three  positive  cutaneous  and  conjunctival  reactions  (eighteen 
of  which  had  hereditary  connections)  (about  80  per  cent.). 

Schubert,  in  seven  doubtful  cases,  obtained  three  positive 
conjunctival  reactions  (about  40  per  cent.). 

TABLE  V. 

CONJUKCTIVAL    REACTIONS    IN    INTERNAL   DISEASES. 


Author 


Combemale  (p.  34) 
Charmeil  (p.  36) 
Jouveuel  (p.  37) 
Desbonnets  (p.  38) 
Halipre  (p.  38) 
Desplats  (p.  39) 
Letulle  (p.  41) 
Prouff  (p.  42)  . . 
Grillot  (p.  43).. 
Grasset  (p.  46) 
Dujon  et  H.  (p.  46) 
Derscheid  (p.  46) 
Montagnon  (p.  47) 
Braillon  (p.  48) 
Soulce  (p.  50).. 
Metraux  (p.  50) 


kl. 


W.,  1907,  19,  viii 


Citron   (B 

1907) 
Ferreina  (p.  52) 
Uriarte  (?) 
Denys  (p.  53)  . . 
Schubert  (M.  in.   iv.,  ivui,  j 
Klieneberger(3/. »(..  W.,  1907 
Wieus   and   Giinther   (21.    m. 

1907,  No.  52) 
IMainini  (2f.  in.   W.,  1907,  No.  52) 


Xuniber 
of  tuber- 
culous 
patients 


Reaction 


T7.,  1907,  p.  2054) 

""  No.  52) 

W., 


16 

1 

7 

1 

5 

12 

75 

5 

6 

8 

1 

7 

16 

6 

39 

15 

31 

2 
116 

8 
19 

17 
11 

12 


16 
1 
7 
1 
5 
9 

72 
4 
6 


14 
4 
34 
14 
25 

1 

109 

8 

17 

8+2? 

6 

11 


Suspected 


Healtliy 


3 
5 
2 
1 

1 
11 

9 
11 


4 
3 
2 
3 

26 


Total 


435 


391 


45 


76 


45 


8 

2 
19 
8 
1 
1 


72 


earlier  (p.  55) 
Le  Fort  (p.  50) 
Bary  (p.  57)     . . 


Surgical  Cases. 

6              6 

_ 

1 

-     i     -     1 

4              4 

— 

4 

2 

14       !     12 

2 

3 

— 

1 

16 

8 


6 

28 
31 

8 

5 
14 

7 
10 
12 
IS 

9 
40 
44 


8 
24 
38 
26 

48 
397 


N.B.  —  Tkie  pages  indicated  refer  to  the  publication  of  von  Pirquet. 

Schenck  and  Seiifert  in  twenty  doubtful  cases  obtained 
six  (30  per  cent.)  positive  conjunctival  reactions  at  the  first 
instillation,  six  (30  per  cent.)  at  the  second  instillation,  three 
(15  per  cent.)  at  the  third  instillation.     Total  75  per  cent. 


( 


62  THE  OPHTHALMIC  AND  CUTANEOUS 

Citron  obtained  80  per  cent.,  Eppenstein  40  per  cent., 
conjunctival  reactions  in  doubtful  cases. 

Further  investigations  are  recorded  in  Table  V.,  which 
surveys  the  results  obtained  by  the  other  authors  not  men- 
tioned in  the  text. 

Our  own  investigations  may  be  found  in  the  tables  printed 
a  few  pages  previously.  They  contain  the  results  of  the 
cutaneous  and  conjunctival  reactions,  at  the  same  time  dis- 
tinguishing between  the  different  stages  of  tuberculosis.  Tbis 
way  of  tabulating  has  several  advantages. 

THE    REPETITION    OF    THE    REACTION. 

As  in  all  cases  in  which  processes  of  hypersensibility  play 
a  part  a  reaction  cannot  be  repeated  without  producing  a 
decided  change.  Von  Pirquet  has  found  that  in  some  cases 
in  which  the  cutaneous  inoculation  was  repeated  the  reaction 
increased  in  strength  and  became  positive  where  first  it  had 
been  negative  {Wie)i.  Jdui.  Wochenschr.,  1907,  No.  38).  His 
remarks  only  refer  to  the  cutaneous  reaction,^  but  the  hyper- 
sensibility is  even  much  more  pronounced  in  the  conjunctival 
reactions.  A  great  deal  in  regard  to  this  matter  has  already 
been  collected,  and  we  attach  to  it  great  theoretical  signifi- 
cance. We  will  only  point  out  here  that,  for  purposes  of 
diagnosis,  one  may  not  repeat  the  reactions  ad  lib.,  since 
in  doing  so  unforeseen  conditions  arise.  I  do  not  mean  to 
say  that  repetitions  should  never  be  allowed  ;  the}^  are  quite 
harmless  as  far  as  the  patient  is  concerned  and  are  at  any 
rate  of  scientific  and  even  (although  to  a  very  limited  extent) 
of  diagnostic  value. 

The  Significance  of  the  Positive  Result  of  the  Conjunctival 
Reaction  when  Repeated. — As  more  extensively  dealt  with  in 
the  Theoretical  Part,  I  am  of  opinion  that  the  positive  result 
of  the  reaction,  when  repeated,  indicates  the  presence  of 
latent  tubercular  centres.  The  circumstances,  however,  have 
to  be  taken  into  account  in  so  far  as  the  reaction  occurring 
after  repeated  instillation  may  not  be  simply  registered  as 
positive  and  be  used  as  such   unreservedly  for  the  diagnosis 


'  Compare  the  chapters  on  the  application  of  the  reaction  in  the 
diseases  of  children  and  in  dermatology,  in  which  we  refer  to  special  obser- 
vations of  scrofuloderma-like  changes  in  cases  where  the  cutaneous  reac- 
tion has  been  repeated. 


DIAGNOSIS    OF   TUBERCULOSIS  63 

of  tuberculosis.  The  neglect  of  this  rule  explains,  for  instance, 
why  Eppenstein  obtained  100  per  cent,  reactions  in  cases 
of  tuberculosis ;  he  fails  to  tells  us,  however,  in  how  many 
healthy  individuals  a  similar  result  was  obtained  after  re- 
peated instillation.^  Fritz  Levy  is  the  first  in  Germany  who 
has  called  attention  to  the  fact  that  hypersensibility  results 
when  the  conjunctival  instillation  is  repeated  (quoted  after 
Cohn,  Berl.  kiln.  Wochenschr.,  1907,  who  confirmed  his 
remarks  by  personal  observations).  These  observations  are 
of  importance  because  the  repetition  of  the  subcutaneous 
injection  of  tuberculin  is  to  be  objected  to  on  the  same 
theoretical  grounds.  This  will  be  more  fully  expounded  in 
the  Theoretical  Part. 

As  may  be  expected  the  literature  on  the  subject  provides 
us  with  a  few  analogous  remarks.  Auberet  and  Magne 
{Journal  de  Medecine  de  Bordeaux,  August  15,  1907)  have 
made  similar  observations.  Petit  is  of  opinion  that  these 
observations  detract  from  the  value  of  the  ophthalmic  reaction 
and  is  delighted  to  find  that  Mongour  and  Laude  (see  Bulletin 
Medical,  September  4,  1907,  p.  G5),  in  ten  cases  have 
instilled  tuberculin  twice,  and,  after  enumerating  these  cases, 
he  concludes  that  only  in  one  case  (which  he  attributes  to 
an  experimental  mistake)  a  change  in  the  reaction  was 
observed  at  the  second  instillation.  Levy,  on  the  other 
hand,  finds  that  hypersensibility  results  in  70  per  cent,  of 
his  cases  ;  it  seems  to  take  at  least  three  days  to  appear. 
Cohn  has  confirmed  Levy's  observations  for  twenty  cases 
(the  percentage  is  not  given),  and  he  beheves  that  there  is 
only  a  difference  of  degree  in  the  production  of  hypersensi- 
bility between  non-tuberculous  and  tuberculous  individuals, 
in  so  far  as  in  tuberculous  individuals  the  reaction  after  the 
second  instillation  is  a  very  strong  one.  Generally  speaking, 
I  agree  with  him,  except  that,  according  to  my  own  conception, 
non-tuberculoics  individuals  do  not  produce  the  hypersensibility 
reactions,  but  that  it  would  be  better  to  distinguish  between 
active  and  latent  tuberculosis  than,  like  Cohn,  between  tuber- 
culous and  non-tuberculous  cases.  I  have  embodied  my 
reasons  for  this  view  in  the  Theoretical  Part,  and  here  I  will 


*  As  mentioned  before,  bis  table  does  not  show  in  bow  many  cases  be 
has  x'epeated  the  reaction  in  chnically  health}'  individuals.  At  all  events 
the  number  of  positive  results  obtained  by  him  in  healthy  persons  is  a 
very  small  one. 


64  THE  OPHTHALMIC  AND  CUTANEOUS 

confine  myself  to  quoting  Cohn  himself :  "  In  the  course  of  life 
hypersensibility  is  acquired  in  the  same  way  as  the  capacity 
for  cutaneous  reaction  by  von  Pirquet's  method.  According 
to  a  communication  by  Dessauer  infants  never  react,  not 
even  after  a  second  and  a  third  instillation." 

The  Reinflammation  of  the  Reaction  Sjiots. — It  is  a  remark- 
able fact  that  the  spots  where  the  reaction  had  taken  place 
become  reinfiamed  when  afterwards  tuberculin  is  injected 
subcutaneously.  This  is  equally  true  for  the  cutaneous  as  for 
the  conjunctival  reaction.  A  great  number  of  our  own  inves- 
tigations support  this  statement.^  Petit  has  also  mentioned 
a  few  cases  which  have  been  communicated  by  Slatineano 
and  Guerin.^  {Bulletin  Inst.  Pasteur,  August  30, 1907,  and  Ree. 
de.  Med.  Veterinaire  d'Alfort,  August,  1907).  According  to 
these  reports  reinflammation  after  subsequent  subcutaneous 
injection  may  sometim.es  also  occur  in  individuals  in  whom 
in  the  first  instance  neither  a  cutaneous  nor  a  conjunctival 
reaction  had  been  obtained.  Since  this  reaction  of  non- 
tciberculous  persons  rests  absolutely  on  the  same  principles 
as  the  primary  reaction  occurring  in  tuberculous  individuals, 
viz.,  on  the  presence  of  tuberculin,  producing  therefore  a 
specific  though  artificial  reaction,  it  seems  to  us  unjustifiable 
to  designate  it  as  fausse  reaction,.  Such  a  designation  would 
not  matter  if  it  were  not  for  the  fact  that  its  adoption  at 
the  same  time  would  cause  false  theoretical  views ;  as  a 
matter  of  fact,  enough  confusion  has  been  caused  already  by 
the  designation  fausse  reaction. 

^  Stadelmann  has  made  the  remarkable  observation  that  the  reinflam- 
mation of  the  reaction  spots  occurs  before  the  general  reaction,  but  as  a 
rule  only  in  such  cases  in  which  a  general  reaction  actually  takes  place. 
In  addition  to  the  above-mentioned  French  authors,  the  reinflammation 
of  the  reaction  spots  after  subsequent  tuberculin  injection  has  also  been 
observed  by  Lenhartz  {Aerztl.  Verein,  Hamburg,  October  29,  1907,  ref. 
Miincli.  med.  Wochenschr.,  1907,  No.  48),  Bandler  and  Kreibich  {Deutsche 
med.  Wochenschr.,  1907,  No.  40),  Fritz  Levy  {Ver.  f.  inn.  Med.,  December 
16,  1907),  and  Baginski  (Berl.  med.  Ges.,  December  18,  1906). 

-  In  France,  Lemaire  in  August  last  pointed  to  this  phenomenon,  and  at 
the  same  time  he  showed  that  the  cutaneous  reaction  may  become  positive 
if  at  the  same  time  tuberculin  is  injected.  Experiments  on  animals  by 
Calmette,  Breton  and  Petit  showed  that  after  great  doses  of  subcutane- 
ously injected  tuberculin  the  conjunctival  reaction  remained  negative, 
whilst  after  small  doses  it  became  positive  {Soc.  de  Biol.,  1907,  No.  28). 
Moro  has  also  observed  positive  cutaneous  reactions  in  scrofulous  children 
when  tuberculin  had  been  injected  subcutaneously  at  the  same  time. 


DIAGNOSIS    OF    TUBERCULOSIS  65 

Hypersensibilitij  of  the  N on- in  stilled  Ei/e.  —  Cohn  has 
observed  that  in  tuberculous  individuals,  after  tuberculin  has 
been  instilled  into  one  eye,  the  other  eye  also  may  become 
hypersensitive.  The  theoretical  significance  of  this  fact  need 
not  trouble  us  here  ;  we  will  only  say  that  this  hypersensi- 
bility  is  to  be  explained  by  the  absorptive  capacity  of  the  con- 
junctiva. Special  attention  must  be  paid  to  this  observation 
since  we  recommend  the  repetition  of  the  instillation  in 
the  other  eye  if  a  technical  mistake  is  suspected.  For  this 
reason  the  repetition  on  the  other  eye  would  not  be  alto- 
gether objectionable  from  a  technical  point  of  view ;  but  one 
should  pay  great  attention  to  the  correct  application  of  the 
first  reaction,  since  this  causes  a  change  in  the  original 
reactive  conditions  of  the  body,  lasting  a  considerable  time. 
Fortunately  the  observations  of  Cohn  show  that  such  an 
increase  of  sensibility  after  a  first  reaction  only  occurs  in  cases 
of  actual  tuberculosis,  so  that  after  all  some  diagnostic  value 
is  attached  to  the  observations  in  the  other  eye. 

As  far  as  I  am  aware,  no  good  description  of  this  rein- 
flaming  of  the  reaction  is  found  in  the  literature.  For  this 
reason  I  refer  to  Table  III.  on  p.  58,  where  we  have  indicated 
the  results  of  the  reaction,  as  also  any  symptoms  that  have 
appeared  after  a  subsequent  tuberculin  injection. 

(1)  Case  Sturzbach,  Pav.  1,  who  during  twenty-four  hours 
showed  a  strong  reinflammation  of  the  conjunctival  and 
cutaneous  reactions,  which  had  almost  disappeared.  The 
symptoms  were  more  marked  than  in  the  first  reaction.  Dis- 
tinct pomphi  on  the  skin  surrounded  by  a  strong  red  halo. 
A  late  increase  of  fever  was  remarkable. 

(2)  Lohrk.,  Pav.  1,  in  whom  reactions  were  applied  on 
October  14  and  November  9.  First  reaction  conjunctival 
minus  ;  cutaneous  late  reaction  on  fourth  day.  After  repeti- 
tion, conjunctival  plus  plus,  cutaneous  late  reaction  on  third 
day.  Both  reactions  were  just  traceable  on  November  '23,  on 
which  day  O'OOl  gramme  of  tuberculin  was  injected.  The 
next  morning  a  very  strong  reinflammation  of  the  concluded 
conjunctival  reaction  was  observed  (the  second  eye  remained 
entirely  untouched,  which  is  remarkable  in  view  of  Cohn's 
communications).  Only  the  second  cutaneous  spot  showed 
reinflaming  of  the  reaction.  In  this  case,  too,  fever  only  set 
in  tw^enty-four  hours  after  the  local  symptoms  on  the  reaction 
spots. 

(8)  Altmann.     The  particulars  of  the  cutaneous  and  con- 
5 


66  THE  OPHTHALMIC  AND  CUTANEOUS 

junctival  reactions  may  be  seen  from  the  table.  The  conjunc- 
tival reaction  reinflamed  strongly  about  sixteen  hours  after  the 
tuberculin  injection  ;  not  so  the  cutaneous  reaction.  Again, 
in  this  case,  the  fever  increased  after  about  thirty  hours,  in 
fact,  after  the  appearance  of  th-e  conjunctival  reaction. 

(4)  Koth.  Producing  a  reaction  after  the  second  dose  of 
tuberculin,  the  conjunctival  and  the  cutaneous  reactions  re- 
inflamed. 

(5)  Biirg,  Pavilion  Ga.  The  result  of  the  first  cutaneous 
reaction  was  :  first  day,  plus ;  second  day,  trace ;  third  and 
fourth  days,  minus ;  conjunctival :  first  day,  trace ;  second 
day,  plus  ;  third  and  fourth  days,  plus.  The  other  eye  showed 
slight  inflammation.  After  thirteen  days  the  reaction  was 
repeated  ;  cutaneous  first  to  fourth  day,  plus  ;  (conjunctival 
instillation  in  the  other  [right]  eye),  first  day,  plus  ;  second 
day,  plus,  plus  ;  third  day,  plus ;  fourth  day,  plus.  The  eye 
instilled  on  tbe  first  occasion  again  showed  slight  inflamma- 
tion. Three  times  tuberculin  was  injected  ;  only  after  a  dose 
of  0*005  did  fever  occur  the  next  day  up  to  39"(3°  C,  and  it  was 
only  after  this  dose  that  the  cutaneous  reaction  spot  became 
reinflamed.  This  took  place,  therefore,  before  the  appearance 
of  fever,  but  only  when  a  dose  was  administered  sufficient 
to  cause  a  general  reaction.  On  the  other  hand,  Colin  has 
also  observed  the  reinflaming  of  the  reaction  after  tuberculin 
injection  without  a  general  reaction.  Some  theoretical  value 
may  be  attached  to  the  verification  of  this  fact,  for  which 
reason  1  am  directing  attention  to  it.  Meanwhile  our  own 
observations  have  given  similar  results  in  a  few  cases. 


NOMENCLATURE. 

This  chapter  will  not  detain  us  long.  Von  Pirquet's 
reaction  was  appropriately  designated  by  its  discoverer  the 
cutaneous  reaction,  to  which  name  we  will  adhere. 

Dermo-reaction  by  Rubbing  Tuberculin  into  the  Ski>i. — The 
reaction  obtained  by  Lignieres  and  Berger  {Acad,  des  Sciences, 
Paris,  October  28,  1907)  by  rubbing  tuberculin  into  the  un- 
broken skin  was  also  designated  cutaneous  reaction.  This 
designation  would  have  given  rise  to  a  great  deal  of  confusion 
if  it  had  not  been  for  the  fact  that  this  reaction  found  but 
little  favour,  being  without  advantages  and  involving  more 
work.     It  is,  however,  unjustifiable  on  the  part  of  the  authors 


DIAGNOSIS   OF   TUBERCULOSIS  07 

to  appropriate  the  name  "von  Pirquet's  reaction"  for  their 
own  method,  indicating  von  Pirquet's  method  by  the  name 
dermo-reaction.  It  would  have  been  much  more  appro- 
priate to  designate  the  new  reaction  "  dermo-reaction."  Two 
months  before  these  French  authors  the  same  discover}^  was 
made  by  Moro  and  Doganoff  (Wien.  klin.  Wochenschr., 
No.  3,  1907).  Moro  has  continued  and  elaborated  his  experi- 
ments w'ith  the  salve  reactions  {Milnch.  med.  Wochenschr., 
1908).  We  have  most  thoroughly  tested  his  methods,  but 
we  cannot  find  any  advantages  of  this  "  ointment  reaction  " 
over  the  cutaneous  reaction. 

Conjunctival  Beciction  or  Ophthalmic  Reaction  ? — I  have 
given  the  name  "  conjunctival  reaction "  to  the  process  of 
instilling  tuberculin  into  the  eye.  I  am  very  much  in  favour 
of  maintaining  this  name,  not  only  because  of  its  right  of 
priority  to  the  French  designation  "  ophthalmic  reaction," 
but  also  because  this  name  is  the  more  appropriate,  as  has 
been  distmctlj^  shown,  amongst  others,  by  Levy  {Verein  fiir 
innere  Medizin,  December  16,  1907)  and  Schenck  and  Seiffert 
{Milnch.  med.  Wochenschr.,  November  12,  1907).  The  re- 
action takes  place  on  the  conjunctiva  and  not  in  the  eye. 
The  advantage  of  the  reaction  consists  in  the  fact  that  it 
takes  place  at  a  sensitive,  protected,  and  yet  easily  accessible 
spot,  w^hich  is  not  of  vital  importance  and  which  does  not 
transmit  the  inflammation  to  the  eye.  If  the  name  "  ophthal- 
mic reaction "  expressed  its  nature  in  so  far  as  it  were  to 
include  the  uveal  tract  (iris,  choroid),  the  reaction  could  hardly 
have  been  recommendable. 

The  classical  method  of  the  diagnostic  application  of 
tuberculin,  the  subcutaneous  injection,  had  in  future  best 
be  designated  as  the  subcutaneous  method  and  the  tuber- 
culin subcutaneous  reaction  ;  the  other  methods  occasionally 
applied  are  pulmonary  infusion,  pulmonary  reaction,  tuber- 
culin inhalation,  rectal  reaction  and  the  rectal  method. 

OPINIONS    OF    AUTHORS  ON   THE   CUTANEOUS  AND    CONJUNCTIVAL 

REACTIONS. 

The  inventor  of  the  cutaneous  reaction  (v.  Pirquet)  himself 
did  not  regard  his  method  as  appropriate  for  adults ;  other  inves- 
tigators were  mclined  to  follow  his  example,  and  thus  we  are 
not  able  to  bring  forward  any  favourable  opinions  concerning 
the  cutaneous  reaction  by  other  writers,  except  in  so  far  as 


SCHEMES    FOR    EEGISTER 

The  application  of  the  reaction  is  so  simple  that  no  further  aid  is  necessary.  How- 
ever, if  one  applies  the  reactions  rather  frequently,  and  if  one  desires  to  have  a  synop- 
sis of  one's  material,  one  is  assisted  to  a  considerable  extent  by  a  scheme  for  tabulating 
observations. 

Recent  -observations  have  been  somewhat  confused  ;  one  investigator  speaks  of  a 
positive  reaction  when  he  has  obtained  a  reaction  after  the  first  instillation,  another 
also  when  it  is  obtained  after  the  instillation  has  been  repeated.     The  results  of  one 


Date  of  Application  : 
Sanatorium  : 


SCHEME   FOR  THE   APPLICATION  OF   THE 
By  Professor  Stadelmann 

A.— For   Tuber 


Xame 
and  number 


C'lNJCNCTIVAL 
REACTION 


Suspected 

STAGE 


I     Tubercle 

BACILLI 


-f++ 


Spaces  for  tabulating  any  further  observa 


Subcutaneous 

tuberculin 

injection 


Secondary 
symptoms 


Results  of  fo.st- 

mortem  examination,  or| 

course  of  the  disease  i 


Date  of  Application  : 
Sanatorium : 


SCHEME    FOR   THE    APPLICATION    OF   THE 
By  Professor  Stadelmann 

B. — For  Non-tuber 


Name 
AND  Ndmber 


Hereditary 
Connections 

P  =  Pater 
M  =  Mater 
Pr=Propinqui 


Conjunctival 
reaction 

-       +   -+  +  +  -f 


Days 


Lasting 
reaction 

?  days 


Spaces  for  tabulating  any  further  observa 


Subcutaneous 

tuberculin 

injection 


Secondart 
symptoms 


Results  of  post- 
mortem examination,  or 
course  of  the  disease  1 


ING    OBSERVATIONS. 

investigator,  therefore,  can  hardly  be  compared  with  tliose  of  another,  and  this  is  the 
reason  that,  for  the  most  part,  we  had  to  rely  on  our  own  observations. 

In  order  that  everyone's  observations  shall  become  of  general  value,  we  very  strongly 
recommend  the  following  schemes  for  tabulation,  wliicii  provide  for  all  practical  neces- 
sities, enabling  us  to  at  once  find  a  reply  to  all  questions  of  a  statistical  nature. 

The  schemes  are  published  (in  German)  by  Curt  Kabitzsch  (A.  Stuber's  Verlag, 
Wiirzburg),  and  can  be  ordered  through  every  medical  bookseller.  (Ten  tables,  pro- 
viding for  200  patients'  records,  for  Tid.). 


CUTANEOUS   AND    CONJUNCTIVAL   REACTIONS. 
AND   Dr.  Wolff-Eisner. 

culoiis  Persons. 


Table  No. 


Lasting 
reaction 

'■■  days 

J 

R 

EPETITKiN 

ClTANEOUK 
REACTIO.V 

+       ++    ++  + 

Lasting 
reaction 

?days 

Control 
Eye 

In  the  same 
eye 

In  the  Other 

eye               - 

Repetition 

Whether 

liealthy 

before 

instillation 

Days 

1   1   2   1  3 

4 

Days 

1   1   2   1  3 

4    1    1 

Days 

2    1      3     1      4 

Days 

1   1    2  1  3      4 

1 

1 

1 

1 
i 

1 

1    1 

tious  that  may  be  of  interest  (other  concentrations,  otlier  tuberculin  pi'eparatioiis,  &c.). 


CUTANEOUS   AND   CONJUNCTIVAL    REACTIONS. 
AND   Dr.   Wolff-Eisner. 

ciilotts  Persons. 


Table  No. 


Repetition  is  the 
same  eye 

Repetition  in 

OTHER  EYE 

THE 

CUTANEOl 

+ 

s  Reaction 

+  +   +  +  4- 

Lasting 
reaction 

'?  days 

Repehtion 

Days 

Days 

Control 
eye 

Days 

Days 

1 

2    1    3    1    4 

1 

1 

3 

4 

' 

•2 

3     1      4 

■i-^ 

3 

4 

1 

tions  that  ma\ 

be  of  interest 

(other  concentrations,  other  tuberculin  preparations.  &c.). 

70  THE  OPHTHALMIC  AND  CUTANEOUS 

it  has  to  do  with  children  (see  the  chapter  on  the  diseases 
of  children  in  the  Special  Part).  On  the  other  hand,  a  great 
many  unfavourable  opinions  have  been  expressed.  Abrami 
and  Burnet  i'oand  that  the  cutaneous  reaction  did  not  act 
in  tlie  first  and  second  stages  of  pulmonary  tuberculosis, 
without  being  able  to  explain  the  reason  ;  thus  they  declare 
it  to  be  inconstant  and  irregular,  without  it  being  possible 
to  find  out  why.  There  are  tuberculous  patients  who  do 
not  react  and,  on  the  other  hand,  non-tuberculous  patients 
who  do  react.  The  same  observations  have  been  made  by 
A.  Slatineano.^ 

The  following  opinions  have  been  expressed  concerning  the 
conjunctival  reaction  : — 

LetuUe  :  The  conjunctival  reaction  with  tuberculin  is  a 
simple,  certain,  and  harmless  clinical  method.  The  con- 
clusions to  be  drawn  from  positive  results  are  of  absolute 
value,  unless  the  intensity  of  the  reaction  influence  any 
conclusion. 

Prouff  believes  the  scope  of  the  new  diagnostic  method 
to  be  immense  ;  he  thinks  that  the  ophthalmic  reaction  will 
enable  us  to  show  that  a  whole  Breton  farm  is  attacked  if 
once  tuberculosis  has  gained  an  entrance. 

Grillot  :  "  The  results  are  evident,  and  prove  the  great 
value  of  the  process." 

Grasset  and  Rimbaud :  "  Our  first  few  investigations 
already  make  us  declare  that  we  uphold  the  cutaneous  re- 
action, which  we  believe  to  be  of  the  greatest  service  in  the 
diagnosis  of  tuberculosis." 

Derscheid  :  "  My  experiments  have  been  interesting,  and 
they  confirm  those  of  Calmette." 

Montagnon  :  "  The  results  are  encouraging,  the  process 
is  easy,  and  one  can  understand  that  the  service  to  humanity 
will  be  immense  if  the  reaction  proves  to  be  infallible." 

Braillon  says  he  is  perfectly  convinced  of  the  great 
practical  value  of  the  reaction. 

^  Mainini  {Milncli.  med.  Wochenschr.,  1907,  No.  51)  is,  besides  Stadel- 
niann  and  myself,  the  only  one  who  has  applied  the  cutaneous  reaction 
in  adults  along  with  the  conjunctival.  Feer  (Miincli.  med.  WoclienscJir., 
1908,  No.  1)  reconiniends  a  more  frequent  use  of  the  cutaneous  reaction, 
at  all  events  in  children.  He  starts  from  the  mistaken  assumption  that  the 
conjunctival  reaction  causes  keratitis.  This,  however,  is  due  to  a  special 
hypersensibility,  the  same  phenomenon  which  has  also  been  observed  in 
the  cutaneous  reaction  (see  my  reply  in  Miincli.  uwd.  Wochenschr., 
1908,  No.  2). 


DIAGNOSIS    OF    TUBERCULOSIS  71 

Citron  :  "  The  oplithalinic  reaction  is  bound  to  l)ecome  an 
invaluable  diagnostic  method  for  the  practitioner.  Its  appli- 
cation is  easy ;  dosing  and  taking  the  temperature  are  avoided ; 
it  does  not  cause  any  inconvenience  to  the  patient,  not  even 
in  feverish  cases,  and  is  a  certain  indication  of  tuberculosis. 
The  absence  of  the  reaction,  however,  does  not  prove  the 
absence  of  tuberculosis." 

Denijs  :  "  The  figures  speak  for  themselves  and  encourage  us 
to  further  apply  this  diagnostic  method.  It  has  the  advan- 
tages of  being  simple  and  harmless." 

Bazy  congratulates  himself  on  having  obtained  so  simple 
and  rapid  a  means  for  diagnosing  tuberculosis  ;  he  believes 
that  this  method  will  play  a  very  great  part  in  aiding  the 
diagnosis  of  tuberculosis  of  the  urinary  passages. 

Comby  has  obtained  good  results  with  the  conjunctival 
method  in  300  children  (Sem.  med.,  1907,  p.  371,  in  69  cases  ; 
and  SoG.  d'hop.  sem.  rned.  inf.,  No.  50).  He  declares  "the 
process,  without  reserve,  to  be  simple,  easy,  certain,  and 
harmless  in  healthy  eyes." 

Sicard  {Sem.  med.,  1907,  p.  823) :  "  Seule  I'ophthalmo- 
reaction  est  d'une  application  facile,  et  parait,  dans  ses 
resultats  globaux,  concorder  assez  bien  avec  les  enseigne- 
ments  de  la  clinique.  La  sous-cuti  reaction  et  la  cuti  reac- 
tion sont,  par  contre,  des  procedes  infideles  et  quelquefois 
nocifs." 

Francke,  E.  {Deutsche  med.  Wochenschr.,  1907,  No.  48)  : 
"  The  reaction  never  failed  in  any  case  in  which  it  was  with 
certainty  expected  ;  in  several  doubtful  cases  it  proved  to  be 
of  important  diagnostic  value." 

These  opinions  have  been  cited  partly  after  Petit.  I  do  not 
think  it  necessary  to  quote  any  more  favourable  opinions. 

The  standpoint  I  represent  with  regard  to  these  views 
is  that  the  reaction  can  render  extremely  valuable  services 
in  the  diagnosis  of  tuberculosis,  and  especially  that  it  is  of 
very  high  prognostic  significance.  Thus  far  I  fully  agree  with 
all  these  opinions,  which  lately  have  been  confirmed  by  Levy 
after  considerable  experience.  But  yet  I  still  recommend  a 
critical  and  continuous  investigation  of  the  method,  because 
it  is  not  hundreds  but  thousands  of  patients  who  must  be 
investigated,  and  also  because  in  suspected  cases  years  must 
pass  before  the  significance  of  the  reaction  can  properly  be 
judged.  Our  own  post-mortem  results  speak  distinctly  in 
favour  of   the  method  in  so  far  as  the  conclusions  we  drew 


72  THE  OPHTHALMIC  AND  CUTANEOUS 

from  the  reaction  proved  to  be  correct.  So  far  definite 
opinions  can  only  be  given  in  the  cases  of  healthy  individuals 
and  in  tuberculosis  of  the  first  to  the  third  stage.  I  here 
make  my  standpoint  clear  because  in  France  and  Germany 
a  trend  of  thought  seems  to  gradually  come  into  existence 
which  is  as  far  beyond  the  mark  on  the  one  side  as  the  original 
blind  enthusiasm  vi^as  on  the  other.  This  trend  of  thought 
against  the  reaction  justifies  my  original  cautiousness  in  com- 
municating my  first  discoveries,  w^hich  caused  Calmette  and 
his  followers  to  begrudge  me  the  merit  of  having  created 
this  method  for  clinical  purposes. 

Of  these  critics  we  might  first  mention  Mantoux,  who, 
at  the  French  Congress  for  Internal  Medicine,  in  October, 
1907  (see  Milnch.  mecl.  Wochenschr.,  1907,  No.  49),  expresses 
the  opinion  that  the  ophthalmic  reaction,  whether  positive  or 
negative,  should  be  interpreted  with  great  reserve.  He  arrived 
at  this  conclusion  because  out  of  200  children  under  16,  only 
sixteen  ( =  8  per  cent.)  reacted  positively,  and  of  these  only 
three  could  be  suspected  of  suffering  from  tuberculosis,  whilst 
ten  «o;i-reacting  children  on  clinical  investigation  were  found 
to  be  in  the  first  stage,  according  to  Grancher.  At  the  same 
Congress,  however,  Scherb  (Algeria)  arrived  at  opposite  con- 
clusions. To  him  the  ophthalmic  reaction  represents  a  very 
sensitive  method  of  diagnosis,  and  is  of  special  interest  when 
it  reacts  positively  in  those  cases  in  which  chnically  it  had 
not  been  expected,  or  negatively  where  one  might  have 
expected  the  opposite.  It  seemed  to  him  that  great  benefit 
might  be  derived  from  it  in  the  case  of  infants. 

Barbier  {Soc.  des.  Hop.,  Paris,  December  6,  1907,  ref. 
Sem.  med.,  1907,  No.  50)  has  built  up  a  criticism  of  the 
method  on  the  observation  of  one  patient.  The  latter,  in 
whom  a  positive  reaction  was  obtained,  had  pleuritis ;  the 
'post-mortem  showed  the  cause  of  the  pleuritis  to  have  been 
a  hydatid  cyst  of  the  liver.  Barbier  had  drawn  false  conclu- 
sions as  to  the  nature  of  the  pleuritis  from  the  positive 
reaction. 

Souques  obtained  twelve  reactions  in  fifteen  non-tuberculous 
individuals  which  partly  corresponded  with  the  reactions  ob- 
tained after  subcutaneous  tuberculin  injection.  From  this  he 
concludes  that  the  action  of  tuberculin  cannot  be  specific. 

Sicard  has  found  manifest  tuberculous  changes  post  viortem 
in  two  cases,  although  the  reaction  was  negative,  even  after 
having  been  repeated.  He  recommends  a  certain  reserve  in 
drawing  conclusions,  especially  in  the  case  of  adults. 


DIAGNOSIS    OF   TUBERCULOSIS  78 

Massary,  again,  obtained  very  satisfactory  results.  He, 
however,  obtained  a  positive  reaction  in  a  case  of  general 
carcinosis,  and  therefore  concludes  that  the  conjunctival  re- 
action is  not  infallible  as  a  method  of  diagnosis.  He  only 
attaches  a  certain  value  to  it  if,  positive  or  negative,  it 
corresponds  with  the  clinical  symptoms,  thus  supporting  or 
detracting  from  a  diagnosis. 

Mery  conceives  the  method  to  be  of  importance,  but  not 
absolutely  reliable. 

Salvolini  represents  the  ophthalmic  tuberculin  reaction 
(Riform.  med.,  1907,  No.  4'2)  as  a  good  though  not  absolutely 
reliable  diagnostic  method,  because  it  may  fail  in  distinct 
tuberculosis,  whilst,  on  the  other  hand,  it  may  appear  in  non- 
tuberculous  cases. 

I  have  quoted  all  these  unfavourable  reports  fairly  ex- 
tensively,^ like  the  others  of  a  more  favourable  nature  ;  I 
have  omitted  a  great  number  of  the  latter  so  as  to  avoid  any 
suspicion  of  wishing  to  retouch  the  results.  The  criticisms 
referred  to  find  their  explanation  partly  in  the  fact  that  they 
are  not  sutiiciently  critical,  partly  in  the  somewhat  naive 
conception  that  the  conditions  of  the  reaction  are  so  simple 
that  the  result  simply  and  without  further  thought  indicates 
the  presence  or  absence  of  tuberculosis.  Surely  tuberculosis 
bears  a  somewhat  too  polymorphous  character ;  also  the 
reactive  capacity  differs  too  greatly  in  active  and  latent  tuber- 
culosis. As  far  as  tbe  very  complicated  circumstances  can, 
so  far,  be  understood,  we  have  analysed  them  elsewhere,  and 
the  reader  will  find  that  they  are  rather  more  than  less 
complicated. 

Other  objections  at  once  indicate  a  lack  of  critical  power 
from  a  clinical  point  of  view.  Thus,  for  instance,  the  objec- 
tion of  Barbier,  who  did  not  recognize  the  etiological  condi- 
tions of  pleuritis,  and  who  does  not  contemplate  the  possibility 
that  a  tuberculous  centre  may  be  present  in  the  body,  the 
seat  of  which  could  not,  of  course,  be  indicated  by  the 
reaction.  So  also  Sicard,  who  is  surprised  to  find  tuberculosis 
on  autopsy  which  had  not  been  indicated  by  a  positive 
reaction  ;  and  Massary,  who   mentions  a  similar  observation 

'  Some  objections  have  been  raised  hy  ophthalmologists  {Ophth.  Ges., 
Berlin,  5,  -January  16,  1908).  In  the  cases  referred  to  the  reactions  had  not 
been  applied  accordmg  to  my  principles  ;  they  were  taken  in  most  cases  with 
the  preparation  of  Calmette,  or  they  had  been  applied  to  scrofulous  patients 
or  people  suffermg  with  the  eyes. 


74 


THE  OPHTHALMIC  AND  CUTANEOUS 


without  remembering  how  often  it  has  been  pointed  out  that 
dying  persons  do  not  react,  and  who  does  not  stop  to  consider 
that  in  such  cases  there  is  no  need  for  a  diagnostic  method 
which  is  only  of  value  in  the  initial  stages  of  the  disease. 

DIFFERENT    CUTANEOUS    TUBERCULIN    REACTIONS. 

In  my  first  communication  I  have  advocated  the  use  of 
different  reactions  obtained  with  various  kinds  of  tuberculin  ; 
this  view  has  found  strong  supporters  in  Detre  {Biidapester 
kgl.  vied.  Ges.,  November  11,  1907)  and  Kentzler  {Wie7i.  klin. 
Wochenschr.,  1908,  No.  1).  A  difference  does  not  exist  in  all 
cases  ;  in  our  own  curve  figure  the  different  reactions  take  an 
almost  equal  course  (see  curve  figure). 

Kentzler,  in  order  to  explain  the  difference  produced  by 
the  use  of  human  and  bovine  tubercle  bacilli,  has  experimented 
with  these  as  well  as  with  Koch's  old  tuberculin.  His  results 
are  tabulated  as  follows  : — 


Number 
of  cases 

Koch's 
tuberculin 

Human 
filtrate 

Bovine 
filtrate 

+ 

49 

21 

1 

20 

+ 

- 

+ 

- 

Cases  of  unsuspected  tuber- 1 
culosis                                    j" 

Suspected  tuberculosis 

Pulmonary       .,        1st  degree 
■2nd     ,, 
,,        3rd      ., 

69 

34 

27 
27 
23 

20 

13 

26 

27 

3 

5 
2 

io 

64 
32 

25 

17 
23 

1 
2 

6 

68 

32 

27 
21 
23 

Total  cases  of  tuberculosis    . . 

98 

75 

28 

21 

77 

•• 

98 

It  is  worth  mentioning  that  his  experiments  agree  with 
ours,  at  any  rate  as  regards  the  fact  that  he  found  hardly  any 
positive  reactions  in  the  third  stage  of  tuberculosis. 

He  acknowledges  that  his  investigations  did  not  lead  to 
any  view  as  to  a  possible  difference  between  human  and 
bovine  tuberculosis.  It  seems  to  me  that  this  is  due  merely 
to  technical  mistakes,  resulting  from  an  incorrect  method  of 
application. 

Since  the  author  in  question  himself  mentions  the  existence 
of  a  close  relationship  between  the  different  kinds  of  tubercle 
bacilli,  one  may  assume  a  group  reaction.  For  this  reason 
full  value  must  he  attached  to  the  observation  of  quantitative 
reaction  conditions. 


DIAGiS'OSIS    OF    TUBERCULOSIS  75 

This  very  important  point,  has  been  altogether  neglected 
by  Kentzler.  If  the  way  in  which  he  conducted  his  experi- 
ments had  been  correct,  the  hmuan  and  bovine  tuberculin 
tests  together  would  have  provided  at  least  as  many  positive 
reactions  as  Koch's  tuberculin  alone,  the  latter  being  prepared 
from  human  tubercle  bacilli.  According  to  his  tables,  how- 
ever, this  is  not  the  case  ;  the  reactions  not  only  are  of  very 
much  rarer  occurrence,  but  are  also  much  weaker.  This 
would  have  been  still  more  evident  if  the  tuberculin  and 
filtrate  reactions  had  been  represented  by  a  curve  chart. 

Thus  it  would  seem  as  if  Kentzler  had  used  too  weak  a 
tuberculm,  probably  a  kind  containing  too  few  bacteria,  owing 
to  the  manner  of  filtration  (through  filter  candles)  (see 
our  remarks  on  the  prognostic  significance,  &c.,  Wolff-Eisner 
and  Teichmann,  Berl.  kiln.  Wochenschr.,  1908,  No.  2). 

The  results  of  the  experiments  with  filtered  tuberculin 
proved  the  truth  of  this  conception.  When  our  tuberculin 
was  filtered  through  Berkefeld  candles  fewer  cutaneous  reac- 
tions took  place :  that  is  to  say,  they  did  not  occur  in  indi- 
viduals who  formerly  had  reacted  on  the  same  tuberculin 
unfiltered  ;  if  a  reaction  did  occur  it  always  was  of  far  less 
quantitative  value.  We  (myself  and  Stadehnann)  have  found 
the  same  in  a  very  great  number  of  cases  of  the  subcutaneous 
tuberculin  reaction. 

These  discoveries  show  that  the  tuberculin  reaction  is  not 
a  fermentative  one,  but  is  absolutely  quantitative,  and  there- 
fore it  is  imperative  in  the  cutaneous  and  conjunctival  reac- 
tions to  empirically  prepare  a  concentration  which  will  allow 
the  greatest  diagnostic  and  prognostic  value  to  he  gained  from 
the  reaction.  The  most  acceptable  concentration  seems  to  be 
the  Euete-Enoch  tuberculin  obtained  from  the  Medizinische 
Warenhaus  A.G.  at  Berlin,  Karlstrasse  31 ;  for  the  cutaneous 
reaction  one  should  use  a  25  per  cent.,  for  the  conjunctival 
a  1  per  cent,  concentration.  It  is,  of  course,  possible,  in  a 
case  of  manifest  tuberculosis  in  which  a  negative  reaction  has 
been  obtained,  to  force  the  appearance  of  the  reaction  by 
employing  a  stronger  solution  ;  but  in  view  of  our  explana- 
tions we  do  not  see  any  clinical  advantage  in  this  course  of 
action. 

In  assuming  a  difference  between  bovine  and  human  tuber- 
culosis, these  quantitative  conditions  have  to  be  taken  into 
account.     If  a  patient  reacts  on  active 


76 


THE  OPHTHALMIC  AND  CUTANEOUS 


Tuberculin  of  bovine  tubercle 
bacilli 

Tuberculin  of  human  tubercle 
bacilli 

Solution  1  :       10   +    +    + 
1   ;     100  +    + 
1  :   1000  + 

Solution  1  :       10  +    + 
1  :     100  + 
1  :   1000   - 

one  may  safely  conclude  that  the  disease  is  due  to  bovine 
tubercle  bacilli. 

This  is  the  only  explanation  that  suggests  itself  to  me. 

We  refer  to  the  extensive  publication  on  the  subject  by 
Detre,  Wien.  klin.  Wochenschr.,  1908. 


GENERAL    REACTION    IN    THE    LOCAL    APPLICATIONS    OF 
TUBERCULIN. 

The  principal  advantage  of  the  local  reaction  lies  in  the 
fact  that  it  does  not  cause  a  general  reaction,  as  is  the  case 
with  the  subcutaneous  injection.  In  my  first  communica- 
tion I  mentioned  the  fact  that  general  reactions  may  occur 

after  the  local    application    of 

39  m 1   I  j  f"'      I  I   I  I         tuberculin,  but  they  occur  so 

very  rarel}^  and  even  then  are 

so  insignificant,  that  they  can 

38  I  \  I   '  /  \!   !   M  I  I   '  I   I  only  be  observed  when  specially 

looked  for.      Von  Pirquet,  for 

instance,  has  overlooked  them, 

37 1  I   I   i   ' — ^    \  \   '/^  ^  l>-l        since  he  neglected  to  take  the 

temperature  every  two  hours. 
I  have  added  a  curve  figure, 
3g|  I   I   I   I  I   I   I  I  I  I   I  I   I   I        taken  on  May  6,   1907,  which 

indicates  a  general  reaction 
very  clearly,  the  patient  being 
otherwise  without  fever.  A 
general  reaction,  in  tuberculous 
individuals,  may  also  appear 
when  the  local  reaction  pro- 
duces a  negative  result ;  in  fact 
it  seems  to  occur  preferably  in  this  case.  The  theoretical 
insight  we  have  now  obtained  on  the  subject  makes  this  fact 
fully  comprehensible.  As  a  matter  of  fact,  in  cases  of  fever 
it  is  difficult,  as  a  rule,  to  prove  the  occurrence  of  a  general 
reaction,  and  it  is  in  these  cases  that  the  local  reaction  very 
often  remains  negative. 


35 


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1 

!   1     ,     '   i 

79///3S73ff/3S7Sl 

Reaction  applied  on  May  6,  1907. 
Conjunctival  reaction  + 
Cutaneous  reaction  very  slight. 
General  symptoms  -|- 


DIAGNOSIS    OF    TUBERCULOSIS  i  I 

This  general  reaction  following  the  local  application  of 
tuberculin  is  so  rare,  and  so  insignificant,  that  no  practical 
importance  need  be  attached  to  it.  After  having  proved  its 
occurrence  we  do  not  attach  any  further  importance  to  it. 

Lemaire  mentions  that  in  two  cases  of  fever  a  distinct 
increase  in  the  temperature  was  observed  after  the  cutaneous 
inoculation  ;  also  one  patient,  without  fever,  had  a  temperature 
of  39"5°  C.  after  a  cutaneous  inoculation ;  the  same  tempera- 
ture had  prevailed  a  fortnight  previously  after  a  subcu- 
taneous injection  with  tubercuhn.  Burnet  has  observed  only 
very  slight  general  symptoms.  One  or  two  other  authors 
recently  have  mentioned  the  appearance  of  general  symp- 
toms after  the  cutaneous  and  conjunctival  reactions.  This 
proves  that  my  view  with  regard  to  its  occurrence  is  correct. 


B.— SPECIAL   PART. 

THE     APPLICATION     OF    THE     CUTANEOUS    AND    CONJUNCTIVAL 
REACTIONS    IN    THE    DISEASES    OF    CHILDREN. 

Von  Pirquet  recognized  from  the  very  beginning  that 
the  reactions  are  of  the  utmost  importance  in  the  diseases 
of  children,  since  they  enable  us,  contrary  to  those  in  adults, 
to  detect  the  moment  of  infection  with  an  almost  definite 
certainty.  The  basis  on  which  this  valuation  of  the  reaction 
rests  is  the  fact  that  newly-born  infants  never,  without  excep- 
tion, show  a  positive  reaction.  Prouff  (see  Petit,  p.  75)  did  not 
even  find  a  reaction  m  newly-born  infants  whose  mothers  did 
show  a  positive  result  (fifty-four  cases,  in  twelve  of  which  the 
mothers  had  relapsed). 

We  are  adding  the  results  obtained  in  infants  in  the  form 
of  a  table. 

Bang  and  Xocard,  by  means  of  autopsy,  arrived  at  the 
conclusion  that  in  the  case  of  oxen,  calves  are  never  born  in 
a  tuberculous  condition,  but  only  become  tuberculous  after 
birth.  This  rule  also  holds  good  for  man.  Now  the  most 
important  point  is,  that  infants  who  do  not  give  a  reaction 
are  so  sensitive  to  tuberculous  infection  that  at  a  very  early 
age  tuberculous  infection  simply  means  tuberculosis  followed 


78 


THE  OPHTHALMIC  AND  CUTANEOUS 


by  an  early  death,  that  is  to  say,  that  at  that  age  the  mortality 
of  tuberculosis  equals  100  per  cent.  As  the  age  increases 
the  number  of  positive  reactions  increases ;  and  vice  versa, 
the  percentage  again  decreases  when  death  through  tuber- 
culosis is  near  (after  Nageli,  Virchoio's  Archiv.,  vol.  160),  and 
at  the  age  of  18  months  amounts  to  29  per  cent.  Whilst 
tuberculous  changes  are  never  found  j^ost  mortem  in  the  first 
infant  stage,  the  number  of  such  discoveries  increases  w^ith 
the  age.  Tuberculous  changes  discovered  as  matters  of 
secondary  importance  point,  however,  to  the  fact,  at  all 
events  in  the  majority  of  cases,  that  the  infection  did  not 
show  any  tendency  to  spread,  or  even  that  to  some  extent 
it  has  healed  up  (see  also  Hamburger's  observations,  Wien. 
Min.  Wochenschr.,  1907,  No.  36). 


Authors 

Number 

of 
infants 

Positive 
reaction 

Nega- 
tive 
reaction 

Observations  con- 
cerning positive 
reactions 

Other 
observations 

Prouff     and 

54 

0 

54 

The  mothers  of    12 

Petit  (p.  75) 

of    these    infants 
had  reacted 

Czerny 

? 

0 

? 

— 

— 

Baginskv 

9 

0 

? 

— 

— 

Sperk..' 

109 

1 

108 

— 

Died  in  21st  month 

Langstein   (B. 

100 

1 

99 

Tuberculous  post 

— 

kl.  Tr.,1907, 

mortem 

No.  44) 

Aronade  {Med. 

46 

1 

45 

Hereditarily  con- 

Of    those     reacting 

&L,  1907,  No. 

nected  and  dis- 

negatively, it  was 

51) 

tinctly     tuber- 
culous 

found  postmortem 
that  17  were  from 
tuberculosis 

Engel     aud 



1 



See  text . . 

Out  of  100  children 

Bauer  (B.  A- Z. 

22  reacted 

Tr.,1907,  No. 

37) 

The  frequency  of  tuberculosis  in  children  increases  with 
their  age,  especially  between  the  first  and  third  years.  In 
the  first  six  months  of  life  tuberculosis  is  never  found  as 
a  secondary  matter  at  autopsy,  whilst  at  the  age  of  puberty 
the  extent  to  which  it  is  found  is  expressed  by  53  per  cent. 
The  mortality  curve  of  tuberculosis  of  course  takes  an 
inverted  course,  giving  100  per  cent,  for  the  first  half  year 
of  life,  descending  to  50  per  cent,  at  puberty,  and  showing 
tuberculous  changes.  Healed  up  cases  of  tuberculosis  have 
not  been  known  to  occur  before  the  age  of  3  to  4  years, 
and  become  more  and  more  frequent  as  the  age  increases. 


DIAGNOSIS    OF    TUBERCULOSIS 


79 


Von  Pirquet  expresses  his  view  with  regard  to  the  dia- 
gnostic value  of  the  cutaneous  reaction  as  follows  {Wien. 
klin.    Wochenschr..   1907,  No.    38)  :     "  The   positive    result   of 


Months 


OS 

3-G 

6-12 

1  2 

?-4 

h-a 

CIO 

lO-U 

over  7i 

/ 

/ 

/ 

so% 

r' 

^ 

^ 

V 

/ 

/ 

fO% 

0% 

/ 

Frequency  of  tuberculosis  in  988  cases  in  infants  and  children  of  different  agesi 
according  to  von  Pirquet. 


0-3 

3-6 

e-is 

1-2 

2-U 

k-6 

G-10 

10-lU 

over  l!f 

70% 

^ 

V 

so% 

/ 

1 

jj%/ 

30% 



zo% 

I3^S~^ 

-^ 

1 

0'... 

S'i 

__^ 

Frequency  of  latent  tuberculosis  according  to  von  Pirquet. 


the  reaction  indicates  with  certainty  the  presence  of  active 
or  inactive  tuberculous  changes "  (thirtj^-one  confirmed  by 
autopsy,  one  doubtful  case).  The  work  of  Eabinowitsch 
(Berl.    Idin.    Wochenschr.,   1907,    No.    '2),    which    is    provided 


80 


THE  OPHTHALMIC  AND  CUTANEOUS 


with  a  complete  list  of  the  literature  on  the  subject  and  with 
the  cases,  proves  that  one  may  not  conclude  as  to  the  non- 
existence of  tuberculosis  merely  on  the  ground  of  the  signs 
found  at  autopsy.  Organs  which  seem  to  be  healthy  macro- 
scopically  may  be  found  to  contain  tubercle  bacilli  on  micro- 
scopical investigation — the  first  work  on  this  subject  was 
published  by  Orth  in  1876 — and  even  organs  appearing 
microscopically  normal  may  be  found  to  contain  the  bacilli 
in  the  animal  experiment. 


Ages  in  Years. 
9 -a  r,-70 


10      It      1^      13     I'j- 


Frequency  of  active  and  of  latent  tuberculosis  in  children. 

-'  Tuberculosis  on  the  basis     -| \-  Latent  tuberculosis  found 

of     Hamburger's    post-  on  autopsy. 

mortem  results. 

-  o  On  the  basis  of  the  cuta-      o -  o  After  cutaneous  inocula- 

neous  method.  tion. 

Curves  according  to  von  Pirquet. 


In  the  case  of  active  tuberculosis  the  reaction  may  dis- 
appear during  the  last  days  of  life. 

Ebstein,  Ganghofner,  Bayer,  Escherich,  Schick,  Schloss- 
mann and  Binswanger^  have  come  to  the  same  conclusions 
with  regard  to  the  subcutaneous  tuberculin  injection ;  the 
cutaneous  reaction,  therefore,  may  be  regarded  as  a  substitute 
for  the   subcutaneous  tuberculin  reaction.     This  is  of  special 


•  Arcli.  f.  Kinderhcilk.,  1906,  vol.  43,  p.  121. 


DIAGNOSIS    OF    TUBERCULOSIS 


81 


importance  in  the  case  of  children,  because  Baginsky  and 
Neumann  {Berl.  klin.  Woclienschr.,  1907,  No.  9)  and  others 
altogether  disparage  the  subcutaneous  injection  of  tuberculin. 
I  add  a  table  (p.  80)  showing  the  results  of  the  conjunctival 
reaction  in  children  ;  these  results  speak  very  much  in  favour 
of  the  reaction. 

Engel  and  Bauer  {Berl.  klin.  Woclienschr.,  1907,  No.  37) 
fully  agree  with  these  statistics  as  far  as  children  of  a  certain 
age  are  concerned ;  they  differ,  however,  in  the  case  of  infants, 
because  in  one  case,  after  having  obtained  a  positive  reaction, 
they  did  not  find  any  tuberculous  changes  on  autopsy,  and 
in  four  other  cases  with  positive  reactions  they  could  not 
clinically  find  any  symptoms  indicating  tuberculosis,  nor  did 
they  obtain  a  reaction  by  means  of  the  subcutaneous  injection 
of  tuberculin.  In  the  case  of  infants,  therefore,  they  prefer 
the  subcutaneous  tuberculin  injection. 

Diseases  of  Children. 


Xumbpr  of 

tuberculous 

children 

Reaction 

Suspecterl 

H-althy 

+ 

+ 

3 
6 
5 
2 

+ 

Delearde  (p.  59).. 
Ausset  (p.  52)     . . 
Mongour  (p.  64) 
Comby  (p.  68)    . . 

9 

2 
1 
2 

9 
2 

1 
2 

- 

1 
5 

1 

14 
6 
7 
4 

47 
20 
13 

8 

Surgical  Cases. 


Gaudier  (p.  70)  . . 

4 

4 

_ 

4 



1 

9 

^louton    . . 

25 

22 

3 

3 

1 

4 

8 

Bosc 

36 

35 

1 

10 

7 

- 

10 

Moro-Doganoff  and  Schleissner  have  also  obtained 
favourable  results  with  the  cutaneous  reaction.  They  agree 
with  Pirquet  in  their  statements  concerning  the  occasional 
absence  of  the  reaction  in  cachectic  children  and  in  the  final 
stage  of  miliary  tuberculosis  and  of  meningitis  tuberculosa. 

Schleissner  prefers  this  method  to  the  subcutaneous 
tuberculin  reaction,  on  account  of  its  harmlessness.  Occa- 
sionally a  very  high  degree  of  hyper-sensibility  to  tuberculin 
is  found  to  occur  in  children,  especially  in  scrofulous  children, 
and  I  will  here  mention  the  cases  that  have  come  to  my  know- 
ledge. In  adults,  such  a  high  degree  of  hyper-sensibility  is 
apparently  found  only  in  cases  of  local  tuberculosis  of  the 
skin. 

Pfaundler  {Milnch.  Ges.f.  Kinderheilk.,  June  14,  1907)  and 
Moro-Doganoff  {loc.  cit.)  mention  the  case  of  a  four-year-old 
6 


82  THE  OPHTHALMIC  AND  CUTANEOUS 

child  in  which  the  reaction  was  apphed  on  account  of  fever 
after  measles,  and  which  had  an  outburst  of  scrofulides  lasting 
twelve  days,  a  fortnight  after  the  reaction. 

Another  child  showed  a  strong  cutaneous  reaction,  with 
the  formation  of  vesicles,  after  the  application  of  undiluted 
tubercuh'n.  After  eleven  days  a  conjunctivitis  phlyctcienulosa 
appeared  on  both  eyes,  lasting  seventeen  days ;  simultaneously 
a  polymorphous  eruption  not  unlike  lichen  scrofulosum  made 
its  appearance. 

The  same  thmg  was  found  in  the  case  of  a  nine-year-old 
child  suspected  of  pulmonary  tuberculosis,  fifteen  days  after 
a  cutaneous  inoculation  with  25  per  cent,  tuberculin.^ 

So  also  a  two-year-old  child  with  coxitis  and  morbilli 
showed  conjunctivitis  phlyctsenulosa  a  fortnight  after  the 
cutaneous  reaction ;  another  two-year  old  child,  ten  days  after 
a  strong  cutaneous  reaction,  had  a  re-inflammation  of  a  past 
conjunctivitis  phlyctcenulosa  and  of  two  scrofulo-dermata. 

Also  Engel  and  Bauer  {Berl.  klin.  Woclienschr.,  1907,  No. 
37)  have  noticed  strong  reactions  in  scrofulous  patients ; 
sometimes  they  even  observed  tubercle-like  formations  after 
cutaneous  inoculations  (see  the  following  chapter). 

THE    APPLICATION    OF    THE    REACTIONS    IN    DERMATOLOGY. 

Dermatologists  have  mostly  used  the  cutaneous  inoculation, 
which  obviously  is  more  natural  to  them  than  the  conjunctival 
reaction.  As  far  as  my  knowledge  goes,  dermatologists  have 
never  published  any  results  obtained  with  the  latter.  The 
results  obtained,  however,  concur  with  our  own  observations. 
Bandler  and  Kreibich  have  obtained  thirty-four  positive  re- 
actions out  of  thirty-eight  cases  of  local  cutaneous  tubercu- 
losis, whilst  in  four  cases  which  were  complicated  by  severe 


^  This  appearance  of  phlyctsenae  not  merely  after  the  conjunctival  but 
also  after  the  cutaneous  tuberculin  reaction  induces  me  to  refer  in  a  few 
words  to  the  views  as  to  the  origin  of  keratitis  held  by  ophthalmologists. 

The  pui-ely  exogenous  staphylococci  theory  (Burchard  and  Eeich)  we 
may  certainly  regard  as  non-existent. 

It  is  generally  agreed  that  endogenous  stimuli  play  a  part.  Leber  and 
Bruns  obtained  phlyctena-like  formations  by  injecting  dead  tubercle 
bacilli.  But  the  identity  of  these  formations  with  the  real  phlyetenie  is 
disputed.  Staub  assumes  the  existence  of  a  toxin  irritation,  which  should 
have  to  be  supplemented  by  an  exterior  irritation. 

See  Axenfeld,  "  Bakteriologie  des  Auges,"  p.  232.     G.  Fischer,  Jena. 


DIAGNOSIS    OF    TUBERCULOSIS  83 

pulmonary  tuberculosis  the  reaction  was  negative,  in  two  cases 
also  after  subcutaneous  injection  of  tuberculin.' 

The  comnumications  of  all  authors  seem  to  point  to  the 
fact  that  very  strong  reactions  may  always  be  expected  in 
cases  of  lupus  and  skin  tuberculosis ;  this  corresponds  to  the 
well-known  hyper-sensibility  of  the  skin  of  scrofulous  people 
with  regard  to  super-infection  (Bandler  and  Kreibicb, 
Pfaundier,  Moro,  Doganoff,  Oppenheim,  Uffenheimer,  and 
others).  In  a  similar  sense  we  have  to  interpret  the  fact 
communicated  by  Nagelschmidt  and  which  we  have  mentioned 
before,  namely,  that  local  inoculation  with  old  tuberculin 
causes  an  ulcer  in  a  tuberculous  centre  in  the  skin.- 

The  views  concerning  the  pathogenesis  of  a  number  of 
tubercular  affections  of  the  skin,  and  especially  of  scrofulides 
and  their  significance,  are  in  a  continually  vacillating  con- 
dition. Oppenheim  ("  On  Changes  in  the  Skin  in  Adults, 
following  the  Reaction  of  Pirquet,"  Wien.  klin.  Wochenschr., 
1907,  No.  32)  doubts  whether  tubercle  bacilli  are  at  all 
present  in  the  skin  in  a  number  of  tuberculous  processes,  and 
comes  to  the  conclusion  that  tubercle  bacilli  at  any  rate  do 
not  occur  often.  Starting  with  this  view,  he  carried  out 
experiments  in  order  to  find  out  whether,  by  repeated  appli- 
cation of  tuberculin,  changes  analogous  to  those  of  scrofulide 
could  be  obtained.  He  actually  succeeded,  by  repeated  appli- 
cation of  tuberculin  to  the  same  spot  in  the  skin,  in  obtain- 
ing papulous  efflorescence  of  a  soft  consistency,  which  finally 
became  brownish-red  and  flabby,  and  surrounded  with  nodules 
the  size  of  a  millet  seed,  bearing  the  character  of  lichen  scrofu- 
losum. In  another  case  of  lupus  the  pomphi  changed  into 
vesicles,  these  latter  into  sharp-edged  ulcers  which,  notwith- 
standing treatment,  w^ere  still  present  after  a  fortnight.  He 
regards  these  observations  as  somewhat  analogous  to  those  in 
super-infection  in  syphilis  by  Finger  and  Landsteiner. 

Pfaundier,  Moro,  and  others  have  made  similar  observa- 
tions, which  we  have  recorded  in  our  chapter  on  the  reaction 
in  diseases  of  children. 

'  Out  of  sixty-two  noa-tuberculous  skin  cases  thirty-eight  gave  reactions, 
which,  however,  showed  distinct  variations  when  compared  with  those 
obtained  in  lupus  patients. 

-  Nobl  {Wieti.  Jdin.  WochrnHchr..  1908,  No.  1.  p.  27)  describes  a 
reaction  lasting  forty-eight  hours  in  a  scrofulide  of  an  epithelioid  tuber- 
cular character,  showing  an  erythematous  infiltration,  25  niui.  in  breadth, 
with  a  central  vesicular  elevation  the  size  of  a  bean.  Inoculation  in 
a  scrofulide  caused  a  papule  the  size  of  a  bean. 


84  THE  OPHTHALMIC  AND  CUTANEOUS 

Our  observations  enable  us  to  offer  a  solution  to  a  number 
of  problems  still  unsolved  in  dermatology,  and  therefore  we 
will  give  a  short  sketch  of  the  present  state  of  our  know- 
ledge with  regard  to  tuberculosis  of  the  skin,  and  especially 
of  scrofulides. 

Lately  a  great  deal  of  progress  has  been  made  in  diagnosis 
(subsequent  to  the  Finsen  therapy),  and  also  in  the  construc- 
tion of  clinical  symptomatology.  The  progress  made  in  a 
diagnostic  direction  has  gone  hand  in  hand  with  the  use  of 
subcutaneous  tuberculin  injections,  which  were  especially 
used  by  Neisser,  Jadassohn,  Klingmiiller  and  Buschke.  The 
subcutaneous  tuberculin  injection  causes  a  central  reaction 
in  the  case  of  tuberculosis  of  the  skin,  which  is  somewhat 
analogous  to  the  cutaneous  reaction  of  Pirquet. 

The  local  reaction  after  the  subcutaneous  employment  of 
tuberculin  is  most  distinct  in  the  case  of  lupus  ;  it  is  most 
frequently  absent  in  the  case  of  tuberculosis  verrucosa  cutis 
of  infants. 

Besides  lupus  proper,  the  nature  of  which  may  be  regarded 
as  understood,  there  are  other  forms  of  cutaneous  tubercu- 
losis which  must  be  mentioned.  We  may  feel  certain  that 
their  nature  will  soon  become  more  clear  to  us  by  the  frequent 
application  of  the  local  reactions  ;  the  work  done  by  derma- 
tologists with  the  cutaneous  reaction  certainly  embodies  a 
promise  of  this  nature. 

First  we  find  a  description  of  lupus  pernio  by  Jarisch, 
Kreibich,  and  Polland,  which  is  signified  by  infiltrations  of 
a  bluish- red  to  faint  red  colour,  and  which  is  probably  only 
lupus  produced  by  a  disturbance  of  the  circulation.  Then 
there  is  lupus  follicularis  disseminatus,  a  cutaneous  manifesta- 
tion, partaking  at  the  same  time  of  the  nature  of  miliary 
tuberculosis.  This  form  has  a  subdivision,  a  kind  which  only 
occurs  in  the  face,  and  which  has  a  more  favourable  prognosis. 

The  products  of  the  disease  are  of  a  tubercle-like  structure 
found  by  Schassberg,  Bettmann,  and  Finger,  together  with 
tubercle  bacilli.  Jadassohn  showed  that  the  diseased  parts 
are  pathogenetic  with  regard  to  animals  (guinea-pigs),  and 
that  after  they  have  been  removed  by  an  operation  there 
are  recurrences  of  the  disease  ;  Delbanco,  on  the  other  hand, 
believes  in  the  existence  of  toxin  of  tubercle  bacilli  secreted 
by  the  sebaceous  glands. 

All  lupus-like  skin  diseases  may  be  defined  as  diseases 
which  have   a   tendency  to   destroy  the    skin,   forming   scars 


DIAGNOSIS    OF    TUBERCULOSIS  85 

as  they  progress,  showing  remissions,  hut  which  never  heal 
spontaneously.  Quite  contrary  to  these  we  find  clinically  the 
scrofulides,  consisting  of  hnematogenous  dermatosis,  which 
appear  suddenly,  and  are  frequently  symmetrical ;  they  have 
a  more  benign  chai'acter,  showing  but  little  inclination  to 
ulcerate  and  to  form  scars. ^  They  are  found  most  frequently 
in  children  who  have  tuberculosis  in  other  organs.-  Accord- 
ing to  Werther  (Ges.  f.  Natur.  und  Heilk.,  Dresden,  ref. 
Miuich.  7ned.  Woehenschr.,  1907),  diagnostic  significance  is 
to  be  attached  to  these  comparatively  benign  formations, 
which  in  a  pathological  sense  are  to  be  regarded  as  lympho- 
mata,  indicating  tuberculous  formations  in  other  parts  of  the 
body.  To  this  group  belong  folliculitis,  lichen  scrofulosum, 
erythema  induratum  scrofulosum  (Bazin,  Hebra),  in  which 
hard  nodules  appear  in  the  depth  of  the  corium,  the  skin 
over  this  part  having  a  bluish-red  hue.  iVlthough  this  forma- 
tion shows  little  inclination  to  regressive  metamorphosis,  yet 
Hutchinson  has  observed  such  a  process.^ 

I  will  briefly  refer  here  to  three  forms  of  disease  which, 
from  a  pathological  point  of  view,  have  a  tuberculosis-like 
appearance,  and  which  often  have  given  a  positive  result  with 
the  subcutaneous  tuberculin  reaction,  although  it  is  still 
uncertain  whether  they  have  to  be  classed  with  the  group  of 
tuberculous  skin  diseases.  I  am  referring  to  lupus  erythema- 
todes,  pityriasis  rubra,  and  angio-keratoma  Mibelli. 

I  must  mention  that  Bandler  and  Kreibich  have  obtained 
in  one  case  of  lupus  erythematodes,  by  means  of  the  cutaneous 
reaction,  a  distinct,  and  in  another  case  a  weak  reaction,  and 
that  lichen  scrofulosum  and  lichen  syphiliticus  could  not  be 
distinguished  by  means  of  the  reaction,  probably  on  account 
of  the  fact  that  both  affections  are  of  a  scrofulous  nature. 


'  It  may  be  of  interest  to  mention  in  this  connection  that  L.  Dor,  jun. 
(XVIII.  Congr.  de  la  Soc.  Frang.  d'Ophth.,  1906),  regards  the  frequently 
mentioned  phlyctaense,  as  also  episcleritis  and  a  few  tubercles  on  the 
choroid,  as  scrofulides,  at  the  same  time  distinguishing  between  tubercu- 
losis and  paratuberculosis.  Dr.  Emil  Levi,  of  Stuttgart,  to  whom  I  am 
indebted  for  this  communication,  does  not  know  what  the  material 
demonstrating  these  distinctions  consists  of. 

-  See  also  Stock,  "  Tuberculosis  as  Etiology  of  Chronic  Inflammations," 
Grafe's  Archiv,  vol.  66,  i. 

'  The  scrofulide  question  at  present  occupies  the  centre  of  dermato- 
logical  discussion.  It  monopolized  nearly  the  whole  time  of  the  Convention 
of  the  Wiener  dermatolog.  Ges.  on  November  6,  1907  (see  Wien.  Min. 
Wochenschr.,  1908,  No.  1) 


86  THE  OPHTHALMIC  AND  CUTAKEOUS 

111  order  to  decide  the  question  concerning  the  nature  of 
the  lichen  and  the  hipus  erythematodes,  widespread  investi- 
gations have  to  be  carried  out  in  view  of  the  frequency  of 
tuberculosis. 

In  most  of  the  affections  referred  to,  tubercle  bacilli  have 
been  found,  and  reaction  results  have  been  obtained.  Bacilli, 
however,  are  found  so  rarely  in  these  cutaneous  tuberculous 
affections  that  almost  every  case  has  been  published.  For 
instance,  Jacobi  and  AVolff  have  found  tubercle  bacilli  in 
lichen  scrofulosum,  and  Jacobi,  Pellizari,  and  Haushalter 
have  obtained  positive  animal  tests  in  this  disease.  Philipson 
and  Macleo,  and  Ormsby  have  found  tubercle  bacilli  in  the 
case  of  folliculitis ;  Thibierge  and  Eavaut,  Colcott  Fox,  and 
Carle  Lyon  have  observed  animal  pathogenesis  in  erythema 
induratum. 

These  discoveries,  however,  are  so  isolated  that  the  tubercle 
toxin  theory  may  be  maintained,  which  declares  that  the  skin 
affections  in  question  are  caused  by  the  secretions  of  toxins 
which  the  tubercle  bacilli  have  secreted  in  another  part  of  the 
body.  The  principal  exponents  of  this  theory  are  Delbanco, 
Hallopeau,  and  others.  Finally,  Klingmiiller  thought  to  have 
definitely  settled  the  question  when  he  obtained  the  same 
signs  in  people  who  were  suffering  with  such  affections  of  the 
skin  by  means  of  tuberculin  passed  through  Berkefeld  candles. 
It  is  possible  that  our  investigations  may  solve  the  question 
as  far  as  the  toxin  theory  is  concerned,  especially  if  one 
considers  the  fact  that  tubercle-like  changes  in  the  skin  can 
be  obtained,  not  once  but  repeatedly  by  employing,  tuberculin. 
But  after  the  results  obtained  in  our  experiments  we  are  of 
the  same  opinion  as  Jadassohn  in  replying  to  the  experiments 
of  Klingmiiller,  viz.,  that  tuberculin,  even  after  having  been 
filtered  through  Berkefeld  candles,  may  still  contain  particles 
of  tubercle  bacilli,  perhaps  of  ultra-microscopic  size.  From 
our  point  of  view  there  are  no  essential  differences  between 
living  and  dead  tubercle  bacilli ;  and  those  differences  that 
undoubtedly  do  exist  find  their  explanation  in  the  fact  that 
the  living  tubercle  bacilli  propagate,  and  thus  exercise  a 
quantitatively  stronger  action  of  longer  duration.  In  the  case 
of  scrofulides  the  most  probable  explanation  is  that  tubercle 
bacilli  are  drawn  haemotogenously  from  another  tuberculous 
centre  of  the  body,  and  undergo  bacteriolysis  in  the  skin. 
This  view,  w"hich  is  in  harmony  with  the  action  exercised  by 
tuberculin  on  the  skin  of  tuberculous  individuals,  explains  at 


DIAGNOSIS    OF    TUHEKCULOSIS  87 

the  same  time  the  construction  of  tlie  cutaneous  reaction  witli 
its  histological  changes  reminding  us  of  tuberculosis,  and  the 
fact  that  living  bacteria,  or  those  capable  of  life,  are,  com- 
paratively speaking,  found  so  rarely  in  these  centres  of  the 
disease.  It  is  interesting  to  find  that  the  Finsen  therapy 
is  no  longer  regarded  as  acting  specifically,  but — corre- 
sponding with  our  explanations  concerning  the  treatment  of 
tuberculosis — is  looked  upon  as  an  inflammation  which  is 
slowly  progressing  from  the  surface  to  the  interior,  and  which 
naturally  supports  and  increases  the  natural  healing  tendency, 
the  elective  character  of  which  is  based  on  the  processes  of 
sclerosis  which  are  already  preparing  in  the  diseased  tissue 
centres.     (Jadassohn.) 

The  variegated  nature  of  tuberculous  changes  in  the  skin 
causes  Alexander  (who,  by  the  way,  has  supplied  us  with 
an  excellent  collective  referendum  on  scrofulides  in  the  Berl. 
klin.  Wochenschr.,  1907,  Nos.  11-18)  to  exclaim  that,  as  far  as 
tuberculosis  of  the  skin  is  concerned,  dermatologists  continu- 
ally meet  with  inexplicable  symptoms,  not  only  in  regard  to 
localization,  but  also  with  reference  to  the  different  ways  in 
which  the  skin  reacts  when  the  same  virus  is  implanted. 

The  employment  of  the  local  tuberculin  reactions  may  do 
away  with  these  problems  ;  in  a  diagnostic  sense,  as  has 
already  been  fully  explained  ;  and  in  a  theoretical  sense,  b}^ 
showing  us  that  the  reaction  in  the  body  does  not  take  an 
arbitrary  course,  but  follows  certain  laws  of  hypersensibility. 
which  we  have  elucidated  in  another  part  of  this  work,  and 
which  only  need  be  applied  by  expert  knowledge  to  the  mani- 
festation of  tuberculosis  of  the  skin,  especially  to  that  of 
scrofulide,  in  order  to  do  away  at  once  with  practicall}'  all 
problems. 

(Added  during  revision.)  Pick  has  expressed  himself  in 
a  similar  way  at  a  meeting  of  the  Yerein  fur  innere  Medizin 
on  January  20,  1908. 

THE    APPLICATION    OF    THE    REACTION    IN    OPHTHALMOLOGY. 

The  cutaneous  reaction  has  not  yet  been  employed  very 
much  in  ophthalmology,  although  its  employment  here  is 
very  much  to  be  recommended,  for  reasons  to  be  dealt  with 
further  on. 

The  conjunctival  reaction,  on  the  other  hand,  has  been 
extensively  used.     Calmette  has  mentioned  affections  of  the 


88  THE  OPHTHALMIC  AND  CUTANEOUS 

conjunctiva, .  especially  conjunctividse,  as  contraindications. 
In  another  part  of  this  book  we  have  already  mentioned  that 
we  do  not  recognize  these  contraindications,  since  we  have 
never  in  these  affections  been  able  to  observe  any  undesirable 
secondary  symptoms  caused  by  the  use  of  the  conjunctival 
reaction.  Calmette,  however,  recommends  the  free  use  of  the 
reaction  in  affections  of  the  interior  of  the  eye,  also  in  the 
case  of  tuberculosis,  in  view  of  the  good  service  it  may  render 
to  the  ophthalmologist.  And,  indeed,  the  method  has  already 
been  applied  in  a  good  many  cases.  Petit  has  collected  the 
different  results  obtained  by  this  method,  and  he  distinctly 
says  that  it  has  never  produced  any  harmful  results.  In  fact 
Painblan  and  Brunetiere  maintain  that  the  local  instillation 
of  tuberculin  in  the  eye  makes  us  expect  therapeutic  effects. 
Stephenson,  by  means  of  this  method,  diagnosed  the  existence 
of  tuberculous  centres  in  cases  of  eye  disease,  and  praises  the 
reaction  for  enabling  us  to  ascertain  the  tuberculous  nature 
of  affections  of  the  eye  (iridocyclitis,  scleritis,  chorioiditis)  the 
etiology  of  which  would  otherwise  have  been  somewhat  ob- 
scure. Furthermore,  Aubaret  and  Lafon  have  had  favourable 
results  in  isolated  tubercles  of  the  choroid,  in  enchymatous 
keratitis  in  suspected  affections  of  the  nasal  lachrymal  ducts, 
in  kerato-conjunctivitis  phlyctsenulosa,  in  interstitial  kera- 
titis, and  in  chronic  iridocyclitis.  In  two  of  Stephenson's 
cases  the  results  of  the  reaction  corresponded  with  the  results 
m  cases  of  subcutaneous  tuberculin  injection.  Painblan's 
positive  results  in  cases  of  conjunctival  tuberculosis  and  of 
phlyctaBnge  are  worth  mentioning.  Morax  {Soc.  des  Hop., 
December  6,  1907)  is  of  opinion  that  if  tuberculin  is  instilled, 
if  there  is  conjunctival  tuberculosis,  graver  symptoms  maij 
occur ;  but  in  the  case  of  uveal  tuberculosis  this  method, 
according  to  the  unanimous  opinion  of  ophthalmologists,  is 
quite  harmless. 

In  our  chapter  on  Contra-Indications  we  had  occasion  to 
mention  a  few  cases  in  which  the  employment  of  the  con- 
junctival reaction  has  given  rise  to  unfavourable  and  even 
grave  results.  I  will  refer  here  to  this  part  and  adduce  a  case 
of  Barbier  (Soc.  des  Hop.,  Paris,  December  6,  1907)  in  which 
the  instillation  of  a  drop  of  tuberculin  in  keratitis  led  to  a 
grave  affection  on  both  sides,  resulting  in  ulceration  and  the 
loss  of  one  eye.  With  reference  to  cases  like  these  I  strongly 
advise  not  to  employ  the  instillation  in  the  ordinary  way  in 
cases  of  affections  of  the  interior  of  the  eye,  especially  if 
there  is  a  possibility  of  a  tuberculous  affection  of  the  uvea. 


DIAGNOSIS    OF    TUBERCULOSIS  B9 

One  should  begin  with  very  weak  solutions,  1  in  100,000 
and  weaker,  and  repeat  the  reaction  with  solutions  gradually 
increasing  in  strength.  I  am  not  contradicting  myself  by 
having  recommended  caution  in  diagnostically  judging  re- 
peated instillations,  since  I  am  not  of  quite  the  same  opinion 
as  Levy,  who  altogether  rejects  the  value  of  repeated  instilla- 
tions for  diagnostic  purposes.  French  authors  point  to  the 
therapeutic  action  of  the  local  instillation  of  tuberculin  ;  there 
is  more  likelihood  of  obtaining  therapeutic  results  if  these 
measures  of  caution  are  taken,  and  grave  results  may  be 
regarded  as  being  excluded.^ 

It  would  be  very  desirable  if  this  method  were  commonly 
adopted  in  ophthalmology  in  the  manner  I  have  indicated  : 
for  it  would  be  deplorable  if  this  were  only  done  after  having 
caused  damage  to  this  most  sensitive  organ  in  several  people. 
At  the  same  time  I  believe  that  the  proper  application  in 
ophthalmology  of  the  conjunctival  reaction  has  also  a  dia- 
gnostic use,  since  the  views  concerning  the  frequency  of 
tuberculosis  of  the  eye  are  still  greatly  confused.  According 
to  Groenow  ("  Grafe-Siimisch,"  2nd  ed.,  vol.  ii.,  part  1,  p.  67*2), 
one  case  of  tuberculosis  of  the  eye  occurs  in  4,600  ophthal- 
mic patients.  According  to  Horner  it  is  one  in  4,000, 
and  he  specially  refers  to  tuberculosis  of  the  iris  ;  according 
to  Stephenson  it  is  one  in  1,500,  and  it  is  asserted  that  con- 
junctival tuberculosis  is  the  most  frequent  in  occurrence. 
Helborn  (Berl.  klin.  Wochenschr.,  1907,  p.  898)  finds  one  case 
of  tuberculosis  of  the  eye  in  every  200  ophthalmic  patients, 
and  believes  that  it  occurs  even  more  frequently. 

Such  differences  cannot  be  explained  by  the  difference 
in  the  material.  Even  non-ophthalmologists  can  see  that 
great  difficulties  are  attached  to  the  proper  diagnosis  of  tuber- 
culosis of  the  eye,  and  that  a  great  deal  may  yet  be  expected 
from  our  method. 

It  is  impossible  to  say  offhand  whether  in  the  case  of 
conjunctival  tuberculosis  the  reaction  may  be  applied  in  the 
ordinary  way.  It  is  true  that  there  is  less  danger  in  such  a 
case  than  there  would  be  in  one  of  uveal  tuberculosis,  but 
the  transmission  of  the  disease  to    the  cornea  is  not  always 


'  (Added  during  revision.)  In  the  Paris  letter  of  the  Berl.  Jdin.  Wochcu- 
scJir.,  1908,  No.  2,  it  is  mentioned  that  Lapersonne  warns  against  the  em- 
ployment of  the  conjunctival  reaction  if  the  eye  has  not  been  examined 
beforehand  and  found  to  be  free  from  tuberculosis.  He  therefore  represents 
the  same  views  expressed  by  us  in  the  chapter  on  Contx'aindications. 


90  THE  OPHTHALMIC  AND  CUTANEOUS 

excluded.     It    is   therefore    best    in  such   cases    to    apply  the 
reaction  cautiously. 

(Added  during  revision.)  During  the  meeting  of  the 
Berlin  Ophthalmolog.  Soc.  of  January  16,  1908,  several 
speakers  drew  attention  to  the  fact  that  the  reactions  are 
always  very  strong  in  the  case  of  follicular  catarrh  and 
trachoma.  Since  the  action  of  the  tuberculin  causes  an 
accumulation  of  lymphocytes,  we  can  understand  why  the 
reactions  must  be  a  strong  in  diseases  in  which  there  is 
already  hj'pertrophied  lymphatic  tissue.  For  this  reason  it 
is  desirable  to  use  caution  in  applying  the  reaction  in  such 
cases. 

THE    APPLICATION    OF    THE    REACTION    IN    GYNyECOLOCrY. 

It  is  generally  maintained  that  tuberculosis  in  specific 
g5^n8ecological  diseases  is  comparatively  rare.  Of  course 
tuberculosis  in  other  parts  of  the  body  will  be  found  as  fre- 
quently as  usual,  but  this  only  in  a  secondary  sense,  requiring 
no  further  consideration  when  dealing  with  diseases  of  women. 

In  the  Berlin  University  Hospital  for  Women,  Bumm  and 
Martin  have  conducted  experiments  with  a  view  of  determin- 
ing the  influence  on  the  course  of  tuberculosis  in  artificial 
premature  labour.  They  confirm  the  old  maxim  that  preg- 
nancy and  the  secretion  of  milk  (lactation)  intensify  the 
disease.  For  all  other  than  vital  cases  (oedema  of  the  lung) 
their  advice  is^  not  to  cause  premature  birth  after  the 
seventh  month  of  pregnancy.  Sterilization  is  frequently 
combined  with  artificial  premature  labour  in  order  to  take 
advantage,  in  the  struggle  against  tuberculosis,  of  the  change 
which  takes  place  in  the  metabolism  and  which  takes  the 
form  of  an  increase  in  weight. 

Now  it  is  remarkable  that,  in  cases  of  pregnancy  in  which 
the  conjunctival  reaction  had  produced  a  negative  result 
on  account  of  the  very  unfavourable  physical  condition  of  the 
individual  concerned,  the  reaction  made  its  appearance  after 
the  operation  had  been  performed  :  that  is  to  say.  after  the 
physical  condition  had  imjiroved.  This  fact  constitutes  the 
first    authoritative    confirmation    of    the    correctness    of    our 

'  See  Bumm,  Demonstr.  in  Ver.  f.  inn.  Med.  of  Berlin,  February  24, 
1908:  Cent):  f.  Gyn.,  1908,  vol.  iii.,  p.  75;  Zeitschr.  f.  Gebiirtsh..  vol.  xli., 
p.  428. 


DIA(4N0SIS    OF    TUBERCULOSIS  Ul 

conception  concerning  the  prognostic  significance  of  the  re- 
action. It  is  of  special  vakie,  because  in  this  case  it  is  possible 
to  experimentally  change  the  physical  condition,  which  in  all 
other  cases  can  only  be  tried  along  therapeutic  lines,  though 
often  unsuccessfully. 

Landau,  at  a  meeting  of  the  Berl.  mediz.  Gesellschaft  on 
May  8,  1907,  has  pointed  to  the  fact  that  tuberculosis — some- 
times it  is  true,  in  an  early  stage— was  found  in  about  18 
per  cent,  of  the  preparations  obtained  after  operation.  If  we 
are  assured  from  so  competent  a  side  that  genital  tuberculosis 
is  of  such  frequent  occurrence,  greater  significance  may  be 
attached  to  the  local  reactions  even  in  the  case  of  gynajcology. 
Eecently  Birnbaum,  in  an  extensive  monograph,  has  shown 
the  importance  of  the  subcutaneous  tuberculin  injection  :  his 
arguments  would  also  hold  good  in  regard  to  the  application 
of  the  local  reactions  in  gynaecology. 

THE    APPLICATION    OF    THE    REACTIONS    IN    PSYCHIATRY. 

The  reactions  have  also  found  a  wide  field  of  application 
in  psychiatry,  especially  in  France,  and  a  series  of  interesting 
results  have  been  obtained.  We  will  not  stop  to  mention  any 
facts  which  are  m  harmony  with  the  chnical  observations 
dealt  with  above,  and  which,  therefore,  are  not  of  special 
interest  here. 

Lepine  and  Charpenel  arrive  at  the  conclusion  that  the 
local  reactions  in  the  case  of  dementia  praecox  indicate  the 
presence  of  tuberculosis  to  the  same  extent  as  the  one  shown 
to  exist  by  former  investigators  who  worked  with  other 
methods.  Eaviart  welcomes  these  new  methods  of  diagnosing 
in  psychiatry,  because  the}^  facilitate  the  diagnosis  of  tuber- 
culosis, so  difficult  in  the  demented,  and  also  because  it  has 
been  found  that  tuberculosis  plays  some  part  in  the  etiology 
of  certain  forms  of  dementia.  He  has  also  observed  that  in 
the  case  of  children,  as  well  as  in  the  case  of  adults,  the 
number  of  cases  of  tuberculosis  increases  with  the  length  of 
their  stay  in  the  asjdum.  In  the  case  of  demented  children 
this  increase  corresponds  with  that  in  normal  children,  increas- 
ing with  the  age.  In  adults,  however,  the  increase  is  a  very 
great  one.  Raviart  has  obtained  reactions  in  dementia  in 
74  per  cent.,  in  idiocy  in  64  per  cent.,  and  in  dementia  praecox 
in  60  per  cent.  These  figures  are  remarkable  in  view  of 
the  fact  that  out  of  628  demented    adults  only  43  per   cent. 


92 


THE  OPHTHALMIC  AND  CUTANEOUS 


gave  a  conjunctival  reaction.  fOut  of  66  demented  children, 
64  per  cent,  reacted ;  out  of  38  idiotic  children,  28,  which  is 
practically  the  same  percentage.) 


Period  of  Residence. 
Tears 


80 

70 

60 

SO 

hO 

30 

ZO 

10 
0^0 

0-1 

1-5 

5-10 

10-20 

^*^ 

—  T 

1 

^ 

\ 

\ 
1 

/ 

\ 

/ 

\ 

1 

/ 

1 

/ 

I 

/ 

\ 

/ 

\ 

/ 

\ 

W 

\ 
\ 

Is 

^       ^ 

y 

Period  of  Residence. 
Years 


liO  % 

50  "/o 

't0% 

■30% 

ZO^/o 

W/o 
0°o 

0-1 

1-5 

D-10 

10-20 

More 
than  20 

V 

\ 

\ 

^ 

/ 

^            y' 

^    -MJ 

/  ^^ 

/ 

/ 

+  / 

In  children.  In  adults. 

Increase  of  tuberculosis  during  stay  in  a  lunatic  asylum  according  to  Raviart. 

Positive  Conjunctival  Reactions  per  cent. 

Negative  Conjunctival  Reactions  per  cent. 


THE  APPLICATION  OF  THE  REACTIONS  IN  VETERINARY  SCIENCE 
AND  THE  RESULTS  OBTAINED  IN  ANIMALS  WITH  THE 
REACTIONS. 

The  reactions  have  often  been  applied  in  animals,  but  here 
the  results  were  of  a  much  less  distinct  character  than  in 
man.  A  short  time  after  my  communication  with  regard 
to  the  conjunctival  reaction,  Vallee  {Ac.  des  Sciences,  June  17, 
1907)  obtained  positive  results  with  the  conjunctival  reaction 
in  the  case  of  tuberculous  oxen  and  goats  which  had  taken 
the  infection  in  a  natural  way.  His  reactions  were  a  little 
too  strong  with  a  10  per  cent,  tuberculin  solution,  and  he 
therefore  recommends  the  use  of  weaker  solutions.  The 
results  obtamed  by  Vallee  are  confirmed  by  Moussu.  Arloing 
opened  an  extensive  controversy  in   reference  to   the  results 


DIAGNOSIS    OF   TUBERCULOSIS  93 

obtained  by  Vallee.  He  had  investigated  oxen,  goats,  dogs, 
rabbits,  and  guinea-pigs  which  had  reacted  on  the  sub- 
cutaneous tuberculin  injection.  He  could  not  determine  the 
occurrence  of  a  specific  cutaneous  reaction,  and  he  obtained 
similar  results  when  trying  other  kinds  of  tuberculin.  Vallee 
replied  that  Arloing  had  in  twelve  out  of  nineteen  cases  made 
use  of  other  species  of  animals  than  he,  and  that  the  reaction 
was  positive  only  in  naturally  infected,  and  not  in  experi- 
mentall}^  infected  animals. 

This  reply,  however,  does  not  by  any  means  settle  the 
question,  since  there  is  no  reason  why  the  reaction  should 
be  different  in  artificially  inoculated  animals  and  in  cases 
of  natural  infection.  There  is  more  importance,  however, 
in  his  reference  to  the  technical  difference  in  the  manner 
the  experiments  have  been  conducted.  Arloing  inoculated 
very  superficially,  whereas  Vallee  was  very  careful,  trying  to 
obtain  a  slight  suggillation. 

Lignieres,  again,  has  not  met  with  one  failure  in  the  200 
tuberculous  oxen  in  which  he  has  applied  the  cutaneous  and 
conjunctival  reactions ;  in  health}^  animals  it  was  never  posi- 
tive. The  conjunctival  reaction  was  the  more  sensitive 
(Sem.  mecl,  1907,  No.  40). 

The  other  communications  found  in  the  literature  are  also 
contradictory.  Levy  (Ver.  f.  innere  Medizin,  Berlin,  Decem- 
ber 16,  1907)  did  not  obtain  any  conjunctival  reactions  in 
tuberculous  dogs.  Arloing,  in  four  artificially  infected  dogs 
{Soc.  d.  Biol.,  November  28,  1907),  obtained  in  one  case  only  a 
slight  reaction  ;  also  only  in  one  out  of  four  calves.  However, 
these  were  merely  feeding  experiments,  and  in  most  cases 
no  macroscopic  tuberculous  changes  were  to  be  found  post 
mortem.  An  increase  in  the  temperature  after  the  sub- 
cutaneous injection  of  tuberculin  cannot,  for  our  purpose,  be 
regarded  as  sufficient  proof  of  any  existing  tuberculous 
infection. 

Nobecourt  and  Mantoux  have  obtained  positive  conjunc- 
tival reactions  in  rabbits  if  there  was  slight  infection  with 
tuberculosis  ;  negative  reactions  in  severe  cases  after  in- 
travenous infection  and  after  introducing  tubercle  bacilli  into 
the  stomach.  They  never  obtained  a  positive  cutaneous 
reaction  in  rabbits,  though  Lignieres  speaks  of  having 
obtained    such  reactions. 

Also  in  the  case  of  guinea-pigs  the  conditions  seem  to 
be    rather    complicated.       Joannovics   and    Kapsammer   were 


94  THE  OPHTHALMIC  AND  CUTANEOUS 

never  able  to  detect  definite  tuberculous  affections  by  means 
of  the  cutaneous  and  conjunctival  reactions  in  a  great  number 
of  »uinea-pigs.  Out  of  forty  animals  under  observation  only 
two  gave  a  slight  reaction.  Slatineau  obtained  very  distinct 
reactions  in  tuberculous  guinea-pigs.  Bournet  must  also 
have  obtained  positive  results  in  the  case  of  guinea-pigs, 
since  he  speaks  of  having  investigated  pieces  of  the  skin  of 
guinea-pigs  vs^here  a  reaction  had  occurred.  The  change, 
however,  did  not  seem  to  him  to  have  been  specific,  as  the 
affection  gave  him  the  impression  of  a  burn,  and  also  because 
he  found  a  great  accumulation  of  leucocytes  around  an  eschar 
formation.  Levy  and  myself,  again,  have  obtained  negative 
results  in  guinea-pigs ;  whereas  Klemperer  had  positive  re- 
actions (Ver.  f.  innere  Medizin,  Berlin,  January  (5,  1908). 
Professor  Klemperer  himself  showed  me  one  case  of  a  guinea- 
pig,  infected  by  means  of  sputum  about  eight  days  previously, 
which  gave  a  distinct,  although  not  very  intense,  reaction. 
In  a  few  other  cases,  again,  in  which  he  had  himself  per- 
formed the  inoculation,  the  reaction  was  a  negative  one. 
According  to  the  observations  of  Klemperer,  at  least  three 
days  must  elapse  after  the  infection  before  the  reaction  can 
be  judged.  He  has  not  yet  found  out  at  what  later  time 
it  disappears. 

To  judge  by  the  material  at  hand,  the  reaction  in  the 
»uinea-pig  seems  to  be  somewhat  vacillating,  and  often,  it 
seems,  there  is  a  rapid  reaction  (see  under  that  heading).  If 
it  could  be  definitely  confirmed  that  in  the  guinea-pig  a 
reaction  can  always  be  obtained  in  the  first  stages,  it  would 
pj-QYe — and  this  would  be  corroborated  by  other  observations 
— that  also  in  the  guinea-pig  we  have  a  certain,  though  not  a 
hicrh,  degree  of  reactive  capacity  ;  that  is  to  say,  an  impulse 
resisting  the  infection  with  tuberculosis.  This  is  also  evident 
from  the  fact  that  the  period  between  the  infection  and  the 
death  of  the  animal  varies  from  six  weeks  to  nine  months, 
according  to  the  virulence  of  the  infection.  But  this  does 
not  in  any  way  impair  the  conclusions  drawn  by  us  from 
the  insensibility  of  the  guinea-pig  to  tuberculin,  since  in  the 
case  of  subcutaneous  injection  it  has  been  practically  estab- 
lished that  the  non-infected  guinea-pig  may  be  regarded  as 
insensible  to  the  action  of  tuberculin. 

The  indefiniteness  of  the  observations  concerning  the 
appearance  of  the  reactions  in  animals  is  very  deplorable, 
because  it  prevents  the  practical  application  of  the  local  reac- 


DIAGNOSIS    OF    TUBEliCULOSIS  95 

tions  in  veterinary  science,  though  it  is  probable  that  also  in 
the  case  of  animals  we  may  finally  arrive  at  uniform  results 
governed  by  biological  laws.  It  is  not  impossible  that  animals 
which  seem  to  be  extremely  sensitive  to  infection,  such  as  the 
guinea-pig,  present  other  conditions  of  reaction  than  those 
found  in  man.  It  is,  however,  very  improbable  that  in 
animals  such  as  the  dog  and  the  ox — which,  as  far  as  their 
sensitiveness  with  regard  to  tuberculosis  is  concerned,  are  not 
very  distant  from  man — a  reaction  should  not  be  obtained. 

From  observation  in  man  we  know  how  complicated  the 
course  of  the  reaction  may  be.  In  this  case  we  may  learn 
from  what  takes  place  in  man  (about  whom  we  now  have 
definite  information  to  utilize)  what  happens  in  the  case  of 
animals.  The  experiments  in  animals  carried  out  by  Calmette, 
as  also  our  own  observations  in  man,  show  how  well  the  con- 
clusions we  drew  from  the  apparent  unreliability  of  the 
reaction  in  man  have  been  justified,  and  have  been  corrobo- 
rated by  statements  by  the  writers  on  the  subject.  In  the 
case  of  animals  it  must  also  be  taken  into  account  that  the 
thick  skin  greatly  impedes  the  process  of  the  reaction.  On 
several  occasions  we  have  given  as  our  opinion  that  the 
vascular  arrangement  and  the  capacity  of  absorption  play 
a  very  great  part  in  the  production  of  the  reaction.  It  would 
be  necessary,  therefore,  in  the  case  of  dogs  and  oxen,  to 
introduce  the  tuberculin  into  much  deeper  layers  than  in 
the  case  of  man  :  that  is  to  say,  to  penetrate  deeper  into  the 
dermis.  Klemperer  also  calls  attention  to  the  fact  that 
it  is  necessary  for  the  penetration  of  the  tuberculin  to 
thoroughly  cleanse  the  skin  by  means  of  alcohol  and  ether 
in  order  to  remove  the  sebaceous  matter,  and  that  it  would 
also  be  of  advantage  to  press  a  wad  of  cotton-wool  soaked 
in  tuberculin  on  to  the  wound,  and  to  leave  it  there  for  some 
little  tnue.  According  to  Klemperer's  directions  it  would 
then  be  necessary  to  thoroughly  shave  the  reaction  spot,  and, 
in  the  case  of  guinea-pigs,  to  perforin  the  reaction  on  such 
spots  as  are  covered  with  white  hairs,  since  the  pigment 
present  at  dark  spots  would  impede  the  observation  of  the 
reaction. 

Finally,  we  should  make  mention  of  the  animal  experi- 
ments carried  out  by  Calmette,  Breton,  and  Petit.  The  first 
points  out  that  by  introducing  tuberculin  into  the  peritoneum 
the  relation  of  the  opsonic  index  to  the  normal  may  increase 
or  decrease,   according  to   whether    a  small  or  large  amount 


96  THE  OPHTHALMIC  AND  CUTANEOUS 

of  tuberculin  is  inoculated  (normal  index  0'07  ;  after  1  milli- 
gramme of  tuberculin,  0"38  to  0'52  ;  after  large  doses  [10  to  50 
milligrammes],  0'05  to  0"03).  Further  investigations  show 
that  in  rabbits,  after  injecting  tuberculin  into  a  vein,  a  distinct 
conjunctival  reaction  is  obtained  after  sixteen  hours  if  the 
amount  injected  has  been  small  (2  to  10  milligrammes),  and  no 
reaction  at  all  when  large  masses  were  introduced  (100  to  200 
milligrammes).  If  rabbits  are  infected  by  means  of  living 
tubercle  bacilli,  a  conjunctival  reaction  can  be  obtained  from 
the  third  day  onwards,  increasing  in  the  days  following, 
and  disappearing  after  fifteen  to  eighteen  days,  simul- 
taneously with  the  arrival  of  the  period  at  which  the  weight 
begins  to  decrease,  and  more  severe  tuberculous  changes 
appear. 

The  most  recent  communications  from  a  veterinary  side 
which  have  been  published  since  the  appearance  of  the 
German  edition  fully  confirm  these  views.  (90  to  98  per  cent, 
of  positive  conjunctival  reactions  in  bovine  tuberculosis.) 

Through  the  kind  assistance  afforded  to  me  by  the 
Prussian  Ministry  of  Agriculture,  I  am  now  in  a  position  to 
form  a  personal  opinion  concerning  the  conditions  in  question. 

Our  attention  will  be  directed  first  of  all  to  the  problem 
whether  we  are  enabled,  by  means  of  the  conjunctival  test,  to 
recognize  the  presence  of  tuberculosis  in  such  animals  as  have 
been  previously  injected  with  tuberculin.  It  is  well  known 
that  this  method  is  frequently  employed  to  deceive  the  German 
quarantine  officers,  and  thus  to  introduce  into  Germany 
tuberculous  oxen  which  did  not  react  with  fever  to  the  sub- 
cutaneous tuberculin  injection  on  account  of  the  previous 
treatment  with  tuberculin. 


DIAGNOSIS    OF   TUBERCULOSIS  97 


C— THEORETICAL    PART. 

THE  COMPARATIVE  VALUE  AND  SIGNIFICANCE 
OF  THE  CUTANEOUS  AND  CONJUNCTIVAL 
KEACTIONS. 

In  the  clinical  part  we  have  already  dealt  with  the  clinical 
significance  of  the  reactions,  and  we  only  wish  to  supple- 
ment the  observations  made  there  by  a  few  more  theoretical 
points,  which,  however,  will  prove  of  great  practical  value. 

We  have  seen  that  in  the  case  of  tuberculosis  no  great 
difference  exists  between  the  results  obtained  by  either  reaction, 
and  that  great  differences  are  found  in  those  individuals  who,  on 
the  basis  of  clinical  observation,  are  not  regarded  as  suffering 
from  tuberculosis  or  as  suspected.  To  put  the  matter  concisely, 
according  to  our  own  investigations  one-half,  and  according 
to  the  investigations  of  others  three-quarters  or  more,  of  those 
clinically  unsuspected  of  tuberculosis  react  cutaneously,  whilst 
conjunctival  reactions  according  to  our  own  investigations 
occur  in  one-sixth,  and  according  to  those  of  others  in  an  even 
smaller  number  of  clinically  unsuspected  individuals.  One  is 
almost  tempted  to  discuss  the  question  whether  in  adults  the 
cutaneous  reaction  is  to  be  regarded  as  specific.  Its  specific 
property  is  disputed  by  many,  and  for  this  reason  only  the 
conjunctival  reaction  is  employed  by  them. 

In  the  clinical  part  I  have  left  no  doubt  as  to  my  opinion, 
having  clearly  stated  that  for  purposes  of  clinical  diagnosis  I 
distinctly  prefer  the  conjunctival  reaction  lo  the  cutaneous, 
especially  on  account  of  the  results  obtained  in  health}'  in- 
dividuals. It  is  quite  evident  that  it  is  much  more  likely  that 
one-twentieth  to  one-sixth  of  those  thought  to  be  non-tuber- 
culous should  have  tubercular  centres  in  their  bodies,  than 
one-half,  three-fourths,  or  even  more.  If  all  human  beings 
should  happen  to  be  tuberculous,  the  recognition  of  this  fact 
would  certainly  be  of  scientific  interest,  but  clinically  it 
would  not  have  any  practical  and  diagnostic  value. 

Yet  I  believe  the  cutaneous  reaction  to  be  specific  also  in 
the  case  of  adults.  All  that  has  lately  been  put  forward 
against  the  specific  nature  of  the  cutaneous  tuberculin  reaction 
(Entz,  Wien.  klin.  Wochenschr.,  1908,  No.  12)  is  based  on  false 
theoretical  conceptions.  As  soon  however  as  it  is  assumed 
7 


98  THE  OPHTHALMIC  AND  CUTANEOUS 

that  the  cutaneous  reaction  is  specific,  it  must  at  once  he  ad- 
mitted that  it  is  by  far  the  more  sensitive  of  the  two.  This 
sensitivity  of  the  skin  with  regard  to  tubercuHn  is  certainly 
somewhat  embarrassing,  because,  as  we  have  seen  before,  the 
basis  of  the  reaction  lies  in  the  so-called  hyper-sensibility,  i.e., 
the  rapid  but  very  strong  capacity  on  the  part  of  a  tissue  to 
react  against  the  slightest  irritation.  By  reason  of  its  rich 
blood  supply  and  the  thinness  of  the  epithelium,  the 
conjunctiva  is  certainly  more  capable  of  reaction  than  the 
skin,  and  in  those  who  are  sensitive  to  pollen,  the  con- 
junctiva is  highly  sensitive,  whereas  the  skin  in  this  case  is 
very  slow  in  reacting.  Therefore  in  the  case  of  tuber- 
culin either  special  conditions  prevail,  or  in  the  adult  there 
is  a  widely  distributed  reactive  capacity  on  the  part  of  the 
integument  with  regard  to  derivatives  of  tubercle  bacilli. 
Such  hyper-sensibility  may  sometimes  have  a  very  deep  signi- 
ficance. And  now  we  have  to  consider  whether  this  hyper- 
sensibility  is  naturally  present  in  an  individual,  or  whether  it 
only  occurs  by  reason  of  the  body  having  previously  been 
in  contact  with  tubercle  bacilli  or  their  products. 

Both  these  possibilities  may  be  regarded  as  reasonable.  If 
during  the  experiment  the  body  for  the  first  time  comes  ni 
contact  with  typhoid  or  cholera  bacilli,  the  antitoxin  which 
is  present  in  the  serum  (without  it  being  necessary  for  the 
body  to  have  come  in  contact  with  these  bacteria  before) 
dissolves  the  bacteria,  and  the  action  of  the  poison  thus 
liberated  brings  about  the  signs  of  inflammation.  The  oitlij 
changes  which  take  place  in  the  body  by  coming  in  con- 
tact with  the  bacteria  consist  in  the  fact  that  (1)  the  hyper- 
sensibility  is  increased,  and  (2)  the  process  of  dissolving 
becomes  more  rapid.  Similarly,  it  is  possible  to  regard  the 
reaction  of  the  skin  to  tuberculin  as  virginal ;  that  is  to  say, 
the  first  contact  of  the  skin  with  the  products  of  tubercle 
bacilli.  This  hypothesis  explains  the  fact  that  in  clinically 
healthy  individuals  the  reaction  in  a  great  number  of  cases  is 
a  late  reaction.  This  late  reaction  would  correspond  with 
the  slow  bacteriolysis  and  the  slow  onset  of  the  inflammation 
in  the  above-mentioned  first  typhoid  infection,  resulting  in 
a  long  period  of  incubation,  lasting  eight  days  up  to  the 
appearance  of  the  first  symptoms  in  serum  disease,  which  ni 
the  case  of  re-injection  appear  after  twenty-four  hours  or  even 
less.  Accordingly,  the  late  reaction  would  be  the  reaction  of 
an  individual  who  had    never   before    come    in    contact    with 


DIAGNOSIS   OF   TUBERCULOSIS  99 

tubercle  bacilli  ;  the  early  reaction,  on  the  other  hand,  would 
have  to  be  regarded  as  the  reaction  of  a  body  which  formerly 
had  come  in  contact  with  tubercle  bacilli,  corresponding  to 
the  behaviour  of  the  body  in  the  case  of  re-injection.  Now 
it  is  very  remarkable  that  at  the  first  application  of  the 
reaction  a  great  many  individuals  do  either  show  no  reaction  at 
all  or  a  late  one,  whilst,  if  repeated,  they  give  a  rapid  reaction, 
that  is  to  say,  they  give  a  prompt  reaction  of  hyper-sensibility. 
(See  Pirquet,  Wien.  klifi.  Wochemchr.  1907,  No.  38.)  The 
theory  that  in  the  period  between  the  two  reactions  the  body 
has  become  infected  with  tuberculosis  may  be  altogether  dis- 
regarded for  the  majority  of  cases,  despite  the  fact  that 
Pirquet  refers  to  an  observation  in  which  he  regards  this  as 
having  been  the  case.  If  this  assumption  on  the  part  of 
Pirquet  should  prove  to  be  correct,  his  case  would  have  been 
one  in  which  the  infection  had  occurred  in  a  hospital,  which 
would  involve  us  in  a  discussion  concerning  hygiene  in 
hospitals.  On  the  basis  of  experiments  with  guinea-pigs 
which  were  put  with  advanced  tuberculous  patients,  I  believe 
it  to  be  a  great  mistake  to  place  initial,  and  especially 
suspected,  cases  in  one  room  with  advanced  tuberculous 
individuals,  as  is  the  case  at  any  rate  in  German  sanatoria, 
and  even  in  the  best  appointed  hospitals.  The  clinician 
may  say  he  has  never  observed  infections  originating  in 
the  hospital,  but,  considering  the  nature  of  tuberculosis,  this 
really  does  not  prove  anything. 

In  discussing  this  question  it  must  be  mentioned  that  it 
is  actually  possible  to  produce  hyper-sensibility  by  inoculating 
a  minute  amount  of  foreign  albumin  substance.  We  know 
from  the  investigations  of  Rosenau  and  Anderson  that  in 
animals  a  condition  of  hyper-sensibility  may  be  induced  by 
the  injection  of  very  minute  quantities  of  seram.  If  we  were 
to  assume  the  same  thing  to  occur  in  the  case  of  tuberculin 
(the  production  of  a  condition  of  hyper-sensibihty  by  only  one 
cutaneous  inoculation),  we  would  still  have  to  explain  why 
a  comparatively  very  considerable  percentage  of  individuals 
who  had  not  given  a  positive  result  at  the  first  application 
of  the  reaction  do  not  show  any  hyper-sensibility  when  the 
reaction  is  repeated.  The  percentage  referred  to  is  from  25 
to  50  per  cent.  The  reply  to  this  question  would  be  that 
also  in  the  case  of  serum  disease  a  number  of  individuals 
prove  to  be  insensible  to  repeated  injection,  and  that 
especially   in   the  case  of  hay-fever  it   is  not  the  majority  of 


100  THE  OPHTHALMIC  AND  CUTANEOUS 

individuals  coming  in  contact  with  vegetable  pollen  who 
become  hyper-sensitive,  but  only  a  comparativel}^  small  per- 
centage of  such  individuals. 

So  far  our  train  of  thought  allows  us  to  be  fully  in  favour  of 
the  theory  that  the  late  reaction  is  to  be  regarded  as  a  virginal 
reaction  of  the  body  to  the  first  cutaneous  contact  witJi  tuber- 
culin. The  wide  distribution  of  tuberculosis,  however,  makes  it 
little  likely  that  there  are  many  people  who  have  never  come 
in  contact  with  tubercle  bacilli.  But  even  if  this  be  admitted, 
the  observation  of  Pirquet,  confirmed  by  all  other  writers, 
is  discounted  by  the  fact  that  from  yen.v  to  year  a  greater 
percentage  of  children  react  cutaneousiy.  Newly  born  infants 
do  not  react ;  from  the  first  to  the  third  year  of  age  the  per- 
centage of  reactions  increases  to  such  an  extent  that  at  the 
age  of  from  5  to  10  years  most  children  already  react  on  tuber- 
culin. According  to  v.  Pirquet  {Wien.  klin.  Wocheiischr.,  1907, 
p.  38)  the  post-mortem  results  are  given  of  100  children  in 
whom  the  reaction  had  been  applied.  Half  of  those  who 
were  absolutely  without  tuberculosis  were  in  tlieir  first  year 
of  life  ;  out  of  thirty-three  autopsies  of  children  above  the  age 
of  3,  only  six  v/ere  without  tuberculous  changes. 

Therefore,  the  capacity  to  react  on  tuberculin  cannot  be 
innate  in  man,  but  must  be  acquired.  In  what  way,  then, 
has  it  been  acquired  ? 

It  is  hardly  possible  to  ascribe  the  origin  of  hyper- 
sensibility  to  anything  but  the  fact  that  the  body  has  pre- 
viously come  in  contact  with  tubercle  bacilli.  Since  a  late 
reaction  is  to  be  regarded  as  a  slowed-down  and  diminished 
liyper-sensibility  reaction,  it  would  indicate  the  presence  in 
the  body  of  an  inactive,  perhaps  a  long  since  healed-up  tuber- 
cular centre,  and  that  the  cells  of  the  body  for  a  long  period 
have  had  no  occasion  to  react  on  tubercle  bacilli  or  their 
products,  but  that,  under  the  renewed  stimulus  of  toxin  of 
tubercle  bacilli,  they  had  re-assumed  their  former  reactive 
capacity.  When  the  reaction  is  repeated,  therefore,  a  hyper- 
sensibility  reaction  promptly  occurs.  Our  view  that  late 
reactions  are  due  to  inactive  tuberculosis  is  supported  by 
our  post-mortem  investigations,  positive  cutaneous  reactions, 
especially  late  reactions,  without  conjunctival  reactions,  always 
showing  latent  tuberculous  changes. 

It  is  of  very  great  clinical  importance  if  so  simple  a 
process  (comparing  the  results  of  the  cutaneous  with  those 
of  the  conjunctival  reactions)  enables  us  to  diagnose  correctly 
either  a  healed-up  tubercular  centre  or  active  tuberculosis. 


DIAGNOSIS    OF    TUBERCULOSIS  10  L 

In  the  case  of  the  conjunctival  reaction,  late  reactions  are 
of  very  rare  occurrence.  Also  in  healthy  individuals  they  are 
very  rare.  This  probably  is  due  to  the  blood  supply  of  the 
conjunctiva  as  referred  to  above. 

Summarizing,  we  will  say  that  the  greater  clinical  value 
must  be  attached  to  the  conjunctival  reaction.  If  the 
cutaneous  reaction  be  positive  and  the  conjunctival  negative, 
we  may  diagnose  healed-up  or  inactive  tuberculous  centres. 
This  is  the  reason  w4iy  it  is  desirable  not  to  confine  one's  self 
to  one  method,  but  to  employ  both  reactions  together, 
because  they  complement  one  another  to  a  very  considerable 
extent.  Furthermore,  the  cutaneous  reaction  may  also  be 
regarded  as  a  valuable  control  of  technical  mistakes  in  the 
application  of  the  conjunctival  reaction. 

Since  the  cutaneous  reaction  rather  tends  in  a  positive 
direction,  its  absence  constitutes  a  proof  that  the  conjunctival 
reaction  remains  negative  on  account  of  the  condition  of  the 
patient,  and  not  on  account  of  any  technical  mistake  that  may 
have  been  made. 

That  we  have  been  able  to  arrive  at  these  interesting 
conclusions  by  observing  our  material  is  due  to  the  fact  that 
we  have  always  employed  both  reactions  simultaneousl}^  and 
I  find  satisfaction  in  the  consideration  that  my  conjunctival 
tuberculin  reaction  has  not  done  away  with  the  need  for 
Pirquet's  cutaneous  method. 


THE    REACTION    IN     OTHER    INFECTIOUS    DISEASES. 

After  the  favourable  results  obtained  with  the  local 
reactions  in  tuberculosis,  I  naturally  felt  inclined  to  extend 
my  experiments  to  other  infectious  diseases,  von  Pirquet 
has  already,  I  understand,  tried  to  apply  his  discovery  to 
other  infectious  diseases,  or  at  any  rate  he  has  conveyed 
his  intention  by  word  of  mouth.  My  conjunctival  reaction 
would  be  even  more  adapted  to  such  a  proceeding  by  reason 
of  the  greater  reactive  capacity  of  the  conjunctiva,  and  in 
reality  I  have  carried  out  experiments  in  typhoid  patients  in 
Friedrichshain  long  before  Chantemesse,  and  even  before 
I  gave  publicity  to  the  conjunctival  reaction  with  tuberculin. 
For  this  purpose  I  made  use  of  Picker's  typhoid  "  dia- 
gnosticum," which  is  analogous  to  tuberculin,  but  I  did  not 
succeed  in  obtaining  a  distinct  eruption  on  the  skin  and  on 


102  THE  OPHTHALMIC  AND  CUTANEOUS 

the  conjunctiva.  I  attribute  my  failure  to  the  unsatisfactory 
bacterial  extract  represented  by  Ficker's  reagent. 

A  work  of  Waele  (Soc.  d.  Biol.,  vol.  Ixi.,  No.  28)  deals  with 
the  theoretical  basis  underlying  the  transmission  of  the 
reaction  to  other  infectious  diseases.  From  a  practical  point 
of  view  this  transmission  is  so  obvious  that  Chantemesse  does 
not  even  mention  this  work,  and  it  is  probable  that  he  has 
begun  his  investigations  without  a  theoretical  basis,  and 
merely  on  the  ground  of  my  communications.  Waele 
started  from  the  following  suppositions  :  If  small  collodium 
capsules  filled  with  a  bacteria  culture  are  inserted  under  the 
skin  or  into  the  peritoneum  of  animals  in  accordance  with  the 
well-known  French  method,  its  diffusible  products  are  incor- 
porated in  the  animal  body  in  question.  Toxins  which  are 
affected  by  heat,  and  which  produce  immunity,  do  not  spread 
by  means  of  collodium  capsules.  The  diffusible  products  here 
referred  to  are  (comparatively)  not  affected  by  heat  ;  they 
circulate  and  produce  no  immunity,  but  hyper-sensibility. 
Animals  with  such  capsules  introduced  underneath  the  skin  are 
brought  into  conditions  parallel  to  those  prevailing  in  the 
case  of  infection  with  tuberculosis.  The  substances  spread 
slowly  and  continuously,  and  produce  a  lasting  effect  in  the 
animal.  If,  for  instance,  the  capsule  is  filled  with  tubercle 
bacilli,  a  tuberculin  reaction  is  obtained  in  from  two  to  three 
weeks, ^  if  a  diphtheria,  typhoid,  or  pyogenic  culture  is  brought 
into  the  capsule,  and  if  then  the  animals  are  subcutaneously 
injected  with  the  homologous  products  formed  in  vitro,  a 
temperature  reaction  is  obtained  in  every  way  similar  to  the 
tuberculin  reaction. 

It  could  not  be  decided  at  once  whether,  under  natural  con- 
ditions in  the  case  of  acute  infectious  diseases,  the  time  it  would 
take  the  bacteria  to  act  would  be  long  enough  to  produce  such 
a  result,  or  whether  this  time  for  the  bacteria  to  act  would 
have  to  be  prolonged,  although  in  the  latter  case,  of  course, 
smaller  doses  are  absolutely  necessary.  Although  this  funda- 
mental question  so  far  had  not  been  finally  settled,  it  was  yet 
easy  to  carry  out  experiments  on  the  conjunctiva  of  patients, 
analogous  to  the  conjunctival  tuberculin  reaction.  It  is  hardly 
necessary  to  mention  that  this  form  of  diagnosis  would  be  of 
the  utmost  value  in  cases  of  typhoid,  as  also  in  the  treatment 


*  Analogous     observations     have    quite     recently    been    recorded     by 
Moussu  {Bern,  med.,  1907,  No.  49). 


DIAGNOSIS    OF    TUBERCULOSIS  108 

of  other  infectious  diseases,  and,  if  possible,  of  still  greater 
value  in  combating  the  plague. 

Chantemesse  was  the  first  to  publish  his  excellent  results 
obtained  in  diagnosing  typhoid  by  means  of  the  conjunctival 
method.  He  found  that  it  was  superior  to  the  serum  method, 
which  up  to  then  had  been  the  only  one  at  his  disposal.  In 
sixty-nine  cases  of  typhoid,  both  the  serum  and  the  conjunctival 
reactions  produced  positive  results,  and  in  forty-eight  cases  of 
other  diseases  both  these  reactions  proved  negative ;  in  eight 
cases  the  conjunctival  method  proved  superior  to  the  serum 
diagnosis,  the  conjunctival  reaction  giving  a  positive  result 
three  to  thirteen  days  before  the  serum  reaction. 

"  J'attache  le  plus  de  prix,  parce  que  je  ne  I'ai  jamais  vu 
manquer  chez  les  vrais  typhiques  "  (Chantemesse). 

The  diagnostic  substance  consisted  of  an  extract  of  typhoid 
bacilli,  the  preparation  of  which  rests  on  the  principle  that 
at  a  temperature  of  60°  the  bacteria  are  killed  off,  and  then 
undergo  various  processes  of  precipitation  and  purification. 
(For  further  particulars  see  the  Congress  number  of  the 
Deutsch.  med.  Wochenschr.,  September,  1907,  No.  39,  and 
"  Serotherapie  de  la  fievre  typho'ide,"  Paris  Cour.  d'appel, 
1907.) 

But  very  few  other  authors  have  so  far  carried  out  experi- 
ments in  this  direction.  Kraus,  Lusenberger,  and  Euss  have 
tested  the  substance  in  some  epidemic  of  typhoid  {Wien.  klin. 
Wochenschr.,  1907,  No.  45),  and  have  arrived  at  uncertain  and 
conflicting  conclusions.  Kraus  maintains,  with  Pibram,  that 
at  a  temperature  of  60*^  the  poisons  suppressing  the  reactions 
are  annihilated,  and  that  the  production  of  the  reaction  is 
dependent  on  certain  bodies  of  a  toxin-like  character.  Follow- 
ing up  all  these  precepts,  be  obtained  no  more  than  60  per 
cent,  reactions,  and  he  much  prefers  the  serum  diagnosis. 
Cohn  (Ver.  f.  innere  Med.,  Berlin,  January,  1908)  obtained 
positive  conjunctional  reactions  in  healthy  individuals  by 
means  of  typhoid  extracts,  whilst  Entz  obtained  cutaneous 
reactions  by  the  same  means  in  healthy  individuals  {Wien. 
klin.  Wochenschr.,  No.  13,  1908). 

This  opens  up  one  of  the  most  difficult  problems  concern- 
ing the  science  of  immunity.  Whereas  the  school  of  Pfeiffer 
does  not  admit  the  occurrence  of  toxins,  especially  in  typhoid 
and  cholera,  Kraus  and  others  now  have  published  experiments 
which  go  to  show  that  a  formation  of  toxin  results  from  these 
bacteria.     One    might,    perhaps,    combine    the   two   views  by 


104  THE  OPHTHALMIC  AND  CUTANEOUS 

assuming  the  possibility  that  antitoxins  may  be  produced 
against  a  few  bacterial  constituents  changed  by  the  method, 
whereas  this  would  not  be  possible  with  regard  to  the  un- 
changed bacterium  albumin  (li.  Pfeiffer).  Analogous  to  this 
theory  we  have  the  fact  that  no  antitoxin  can  be  produced 
by  means  of  animal  albumin ;  although  this  may  again  be 
possible  in  a  certain  sense  by  means  of  reduction  (reduction 
toxin,  fatigue  toxin  ;  see  the  works  of  Weichardt,  and  also  a 
collective  referendum  prepared  by  myself  for  the  Zentralhl. 
/.  Bakt.,  vol.  xl.,  part  5,  on  the  basis  of  personal  observations). 
Eisenberg  takes  the  view  that  it  may  be  possible  that  apart 
from  bacteriolysis  the  living  bacteria  secrete  a  poison,  an 
action  not  unhke  the  throwing  off  of  plasmatic  molecules  by 
the  substance  of  the  body.  Furthermore,  the  investigations 
of  Grassberger  and  Schattenfroh  {Wien.  klin.  Wochenschr., 
1907)  show  that  the  production  of  anti-toxin  does  not  under 
ail  conditions  constitute  a  protection  even  wdth  regard  to  the 
kind  of  bacteria  producing  the  toxin  (Kauschbrand).  This 
probably  explains  why,  in  the  experiments  of  Kraus  with 
regard  to  bacterial  infection,  the  activity  of  the  antitoxin  was 
merely  a  moderate  one. 

Whatever  be  the  actual  development  of  this  theory,  the 
difficulties  involved  in  the  application  of  the  conjunctival 
reaction  in  other  infectious  diseases  are  due  to  the  difficulty 
attached  to  the  technical  production  of  the  appropriate  diagnos- 
ing medium — that  is  to  say,  an  appropriate  extract  of  bacteria — 
and  also  to  other  theoretical  difficulties,  which  are  brought 
about  by  the  presence  of  bacteriolysine  substances,  which 
so  far  have  never  had  occasion  to  go  through  the  disease  in 
question.  Personally,  I  have  often  experimented  in  this  direc- 
tion without  having  arrived  at  a  satisfactory  conclusion.  The 
filtrations  obtained  by  means  of  the  Berkefeld  filter  contain,  or 
at  all  events  contained  in  my  own  experiments,  too  little  active 
substance,  which  could  not  be  increased  to  a  sufficient  extent 
even  by  shaking  the  preparation  for  several  days  (before 
filtration)  in  the  shaking  apparatus.  In  making  use  of  the 
bacterial  bodies,  they  have  to  be  heated  to  60°  for  an  hour  in 
the  interest  of  the  patient,  in  order  to  kill  off  the  bacteria  : 
and  if  the  suggestion  of  Kraus,  to  the  effect  that  at  a  tempera- 
ture of  60°  all  active  substances  are  annihilated — which  I  do 
not  beheve  to  be  the  fact  in  all  cases — were  confirmed,  this 
way  of  proceeding  would  never  lead  to  the  end  in  view.  In 
all  these  experiments  it  has  to  be  considered  that  the  great 


DIAGNOSIS    OF    TUBERCULOSIS  10') 

instability  of  the  substance  of  the  bacterial  bodies  (tiie 
endotoxin)  only  makes  it  possible  to  work  for  at  most  twenty- 
four  hours  with  a  newly  prepared  extract.  Recently  I  have 
tried  to  use,  as  a  medium  for  diagnosis,  agressin  exudations 
which  had  been  exposed  to  a  temperature  of  60°  for  an  houi'. 
containing  dissolved  substances  of  bacteria  bodies,  the  solu- 
tion being  prepared  in  such  a  manner  that  the  endotoxic 
action  of  the  substances  in  question  is  not  disturbed  (see  note 
on  agressin,  Zentralhl.  f.  Bakt.,  vol.  xxxviii.,  ref.  Nos.  21-28). 

Although  I  do  not  by  any  means  attach  too  little  import- 
ance to  the  difficulties  which  are  in  the  way  of  applying  the 
conjunctival  reaction  in  other  infectious  diseases,  yet  these 
difficulties  are  to  a  great  extent  of  a  technical  nature,  and  will 
certainly  be  overcome  as  time  goes  on,  considering  the  great 
progress  that  has  been  made  of  late  in  the  production  of 
unstable  bacterial  products. 

In  the  case  of  the  tuberculosis  diagnosis,  the  conditions 
were  extremely  simple.  By  a  comparatively  very  simple 
process — and,  after  all,  it  is  of  very  little  importance  which  of 
the  numerous  methods  at  our  disposal  we  employ — the  sub- 
stance of  the  body  of  the  tubercle  bacillus  can  be  obtained,  and 
can  be  preserved  for  years. 

Putzeys  and  Stiennon  must  also  be  mentioned  when 
deahng  with  experiments  of  this  nature  {Soc.  de  Biol.,  1907, 
No.  27).  Starting  from  the  principle  that  in  animals  with 
glanders  the  subcutaneous  injection  with  virus  of  glanders 
produced  local  symptoms  much  more  distinct  than  those 
obtained  with  tuberculin  in  tuberculosis,  and  at  the  same  time 
considering  the  morphologic  relationship  between  glanders 
and  tuberculosis,  these  authors  employed  in  a  glanders  epi- 
demic old  and  also  fresh  virus  of  glanders  for  the  application 
of  the  cutaneous  and  conjunctival  reactions.  The  reactions 
were  either  altogether  negative,  or  only  very  weak  and 
ephemeral  ;  yet  I  feel  convinced  that,  especially  in  glanders, 
good  results  are  to  be  be  obtained  with  this  method.  Mean- 
while Machel  {Berlin,  klin.  Wochensclir.,  1908,  No.  9)  has 
obtained  very  good  results  in  the  case  of  glanders.  The 
differences  in  the  results  obtained  may  be  due  to  the  vari- 
able material  on  the  market. 

THE  PATHOLOGICAL  ANATOMY  OF  THE  CUTANEOUS  AND 
CONJUNCTIVAL  REACTIONS. 

The  Cutaneous  Beaction. — So  far  we  have  only  been  able 
to  observe  rather  advanced  forms  of  reaction,  viz.,  papules  : 


10()  THE  OPHTHALMIC  AND  CUTANEOUS 

that  is  to  say,  products  with  a  fairly  strong  infiltration.  An 
investigation  of  early  reaction  forms,  therefore,  would  be  very 
desirable.  In  the  cutaneous  reactions  that  have  been  investi- 
gated, great  accumulations  of  lymphocytes  are  found  around 
the  more  deeply  situated  blood-vessels  of  the  skin,  especially 
around  those  vessels  situated  in  the  adipose  layer,  close  to  the 
corium,  and  also  around  those  surrounding  the  sweat  glands. 
Bandler  and  Kreibich  have  in  a  few  cases  observed  distinct 
giant-cells  in  these  accumulations  of  lymphocytes,  but  not 
of  the  Langhans  type,  so  that  the  authors  do  not  regard  these 
formations  as  tubercles,  but  merely  refer  to  them  as  tuber- 
culosis-hke  formations.  Daels  (Med.  Klinik,  1908,  No.  2)  in 
investigating  papules  m  our  material,  has  found,  besides 
ordinary  giant- cells,  also  those  of  the  Langhans  type,  and  there- 
fore regards  the  pathological-anatomic  correspondence  between 
the  formations  produced  by  tuberculin  and  a  tubercle  as  proven. 

Our  own  view  (which  further  on  we  wall  develop  more 
fully)  is  that  no  essential  difference  exists  betw^een  tuberculin 
and  tubercle  bacilli,  but  that  the  action  of  tuberculin  is  solely 
due  to  the  bacterial  bodies  it  contains.  Therefore,  according 
to  this  view,  any  differences  observed  between  the  action  of 
tuberculin  and  that  of  tubercle  bacilli  can  only  be  due  to  the 
endotoxic  substances  present  in  the  tuberculin  being  impaired 
in  the  course  of  preparation,  whilst  all  other  differences  of  action 
can  onl}'  be  explained  by  assuming  the  existence  of  quantitative 
differences.  Now  the  harm  done  to  the  endotoxic  substance 
of  the  tubercle  bacilli  in  preparing  tuberculin  seems  to  be  but 
extremely  minute,  and  for  this  reason  the  difference  between 
the  action  of  tubercle  bacilli  and  that  of  tuberculin  is,  as  a 
matter  of  fact,  merely  of  a  quantitative  nature,  caused  by  the 
fact  that  the  living  bacilli — a  virus  capable  of  multiplying — 
can  always  create  fresh  toxin  to  replace  the  old,  in  this  way 
renewing  and  prolonging  the  action  of  the  poison. 

The  action  of  this  prolonged  influence  of  the  toxin  causes 
necrosis,  and  v.  Baumgarten  actually  demands  the  presence 
of  necrotic  changes  before  diagnosing  tuberculosis,  not  because 
the  tubercle  bacilli  could  not,  in  the  beginning  of  their  activity, 
produce  formations  without  necrosis,  but  by  reason  of  the  fact 
that  also  other  harmful  substances  can  produce  tubercle-like 
formations,  and  that  it  is  only  the  presence  of  necrosis  which 
pathologic-anatomically  enables  us  to  definitely  conclude  that 
living  tubercle  bacilli  are  present. 

In  the  different  forms    of    the    giant-cells   analogous    con- 


DIAGNOSIS    OF    TUBERCULOSIS  107 

ditions  seem  to  prevail.  Without  intending  to  discuss  the 
voluminous  arguments  concerning  the  genesis  of  these  much 
talked-of  giant-cells,  they  seem  to  occur  in  tuberculosis  only  at 
such  places  at  which  a  slow  hacteriohjsis  takes  place  in  which 
the  toxins  are  set  free.  The  actual  reaction  of  the  body  to 
toxins  consists  in  the  accumulation  of  lymphocytes.  These 
correspond  to  the  specific  irritation,  and  the  presence  of  giant 
cells  seems  only  to  refer  to  quantitative  variations  in  the 
action  of  toxins. 

Again,  it  seems  that  it  only  depends  on  quantitative  influences 
of  the  toxic  action  whether  we  find  simple  giant-cells  or  those 
of  the  Langhans  type.  Tuberculin  with  its  fixed  toxin  can- 
not, as  a  rule,  bring  the  tubercles  it  produces  to  necrosis ;  we 
might  regard  the  cells  of  the  Langhans  type  as  the  very  com- 
mencement of  a  necrotic  process.  When  looked  at  from  this 
point  of  view  the  old  theory  of  Weigert  regarding  the  giant- 
cells  as  cells  with  a  commencement  of  necrosis,  seems  to  have 
many  points  in  its  favour,  and  is  supported  by  the  microscopic 
picture  of  the  cell  in  the  centre  of  which  we  still  find  un- 
disturbed tubercle  bacilli. 

The  importance  of  the  quantitative  conditions  of  toxic 
action  in  the  causation  of  necrosis  may  be  seen  from  the  fact 
that  by  inoculation  with  tuberculin  an  ulcer  may  be  produced, 
that  is  to  say,  a  loss  of  substance  through  necrosis,  if  the 
inoculation  is  effected  in  the  lupous  tissue  (Nagelschmidt, 
Deutsch.  mecl.  WochenscJir.,  1007,  No.  40). 

This  conception  of  the  giant-cells  as  products  of  the 
reaction  on  toxic  action  is  all  the  more  important  in  view  of 
the  unreasonable  phagocytic  theories.  Daels,  for  instance 
(Ver.  f.  inn.  Med.,  December  16,  1907),  injected  dead  tubercle 
into  the  carotid,  and  afterwards  found  tubercle  bacilli  (dead 
ones,  of  course,  as  the  experiment  would  show)  in  giant-cells 
(in  the  eye).  On  this  ground  he  concludes  that  the  giant-ceils 
play  a  protective  part  in  the  battle  against  the  tubercle  bacilli. 
This,  of  course,  simply  plays  into  the  hands  of  the  opponents  of 
the  phagocyte  theory,  since  a  protective  function  on  the  part 
of  the  cells  in  question  is  assumed  on  the  basis  of  their  taking 
in  dead  bacterial  substance,  whereas  the  phagocytes  are  sup- 
posed to  attack  only  the  living  bacilli.  These  giant  cells  are 
not  protective  cells  formed  in  the  body,  but  they  have  been 
formed  out  of  other  body  cells  as  a  product  of  reaction  on  the 
part  of  these  cells  against  the  action  of  the  toxin.  They 
disappear  if  the  toxic  action  continues  for  some  tune. 


108  THE  OPHTHALMIC  AND  CUTANEOUS 

From  their  point  of  view  the  pathologists  are  quite  right 
in  using  the  giant  cells  of  the  Langhans  type  for  diagnosing 
a  tubercle,  since  they  cannot  diagnose  tuberculosis  on  the 
basis  of  an  accumulation  of  lymphocytes  ;  but  even  a  very 
careful  pathological  diagnosis  based  on  morphological  factors 
cannot  do  away  with  the  indisputable  fact  that  the  primary 
activity  of  the  tubercle  bacilli  essentially  consists  of  the  forma- 
tion of  a  lymphoma  resulting  from  an  emigration  of  lympho- 
cytes from  the  vessels.  Philipsohn  has  shown  in  an  analogous 
manner  that  in  the  case  of  folliculitis  the  initial  alteration  is 
represented  by  a  small-celled  infiltration  of  the  vascular  wall 
of  the  smaller  vessels. 

In  this  connection  we  will  point  to  the  interesting  constant 
relationship  existing  between  the  tubercle  bacilli  and  tlie 
lymphocytes.  In  the  tuberculous  exudations  of  the  pleura 
on  a  tuberculous  basis,  lymphocytes  are  found  either  exclu- 
sively, or  at  all  events  in  preponderating  masses,  and  the 
same  I  have  found  to  be  the  case  in  the  sputum  of  tuberculous 
patients,  as  indicated  in  another  part  of  this  work.  Together 
with  V.  Torday  I  have  obtained,  in  experiments  with  tuber- 
culin, lymphocyte  exudations  containing  a  percentage  of  80, 
90,  or  even  higher,  of  lymphocytes.  In  the  meningeal 
exudations  Kronig  found  a  preponderating  number  of  lym- 
phocytes in  tuberculous  individuals  ;  and  we  have  only  to 
add  that  a  transformation  of  lymphocytic  forms  into  poly- 
nuclear  formations  enables  us  to  unhesitatingly  pronounce 
an  unfavourable  prognosis. 

Thus  we  find  lymphocytes  in  all  cases  m  which  tubercle 
bacilli  have  come  in  contact  with  the  animal  body,  in  the 
tubercle  ;  in  the  exudations  of  a  tuberculous  etiology  as  a  result 
of  the  action  of  tuberculin  in  experimentally  produced  exuda- 
tions;  and  in  the  skin  papules  obtained  with  tuberculin. 
These  conditions  are  all  the  more  interesting  biologically  by 
reason  of  the  fact  that  lately  Bartel  and  Neumann  have 
vindicated  the  theory  that  lymphocytes  exercise  a  protective 
function  with  regard  to  these  tubercle  bacilli,  by  demonstrating 
that  the  virulence  of  living  tubercle  bacilli  is  distinctly  lessened 
by  the  bacilli  being  brought  in  contact  with  lymphatic  tissue, 
which  corresponds  with  the  observations  of  Brieger,  Kitasato, 
and  Wassermann  with  regard  to  other  bacteria  (cited  aftt-r 
Bartel,  Wien.  Min.  Wochenschr.,  1907,  Xo.  44). 

They  not  only  assume  the  existence  of  connections  between 
tuberculous  infection  and  lymphocytes  in  animals,  but  also  in 


DIAGNOSIS    OF    TUBERCULOSIS  109 

the  case  of  man  ;  to  support  this  view  they  adduce  the  latency 
of  tubercle  bacilh  in  not  specifically  changed  lymphatic  tissues, 
as  also  the  fact  that  in  children  lymph  passages  are  found 
which  are  slightly  reticulated,  whilst  in  adults  there  is  a 
denser  lymph  filter ;  and  further  the  decrease  in  the  resistance 
to  tuberculosis  in  the  status  lymphaticus,  observed  by  Paltauf, 
and  which  is  said  to  distinguish  itself  by  a  strongly  destruc- 
tive growth  of  the  supporting  stroma  and  the  almost  com- 
plete disappearance  of  the  specific  parenchyma. 

I  believe  less  in  the  harm  done  by  the  lymphocytes  to  the 
tubercle  bacilli  than  in  the  role  these  former  play  in  the 
formation  of  connective  tissue  and  the  encapsulation  of  the 
tubercle  bacilli. 

Maciesca  Jelenska  {Brauer's  Beitrdge,  vol.  viii.,  p.  1),  again, 
interprets  these  observations  as  the  formations  of  antitoxic 
substances,  which  of  course  cannot  be  the  case.  The  purpose 
of  the  work  is  to  show  that  in  cases  of  tuberculous  pneumonia 
numerous  plasma  cells  are  found  in  the  perivascular,  peri- 
bronchial, interlobular,  interalveolar  and  subpleural  connective 
tissues,  as  also  in  the  border  regions  of  the  tubercles  ;  the 
author  is  of  opinion  that  these  plasma  cells  are  the  product  of 
haematogenous  lymphocytes  found  in  the  respective  places. 

Nicolai  A.  Bibbin  ("■  Inaugural  Dissertation,"  Berlin,  1907) 
has  found  lymphocytes  in  the  walls  and  capillaries  of  tuber- 
culous glands. 

Despite  the  fact  that  phagocytosis  can  be  demonstrated, 
the  polynuclear  leucocytes  do  not  possess  any  virulence- 
weakening  influence  with  regard  to  tubercle  bacilli. 

As  mentioned  above,  fresh  forms  of  reaction  of  the  skin 
to  tuberculin  have  so  far  not  pathologic-anatomically  been 
investigated.  Clinical  observation  already  shows  that  in  the 
formation  of  the  papule,  exudative  and  infiltrative  processes 
play  a  part,  varying  in  intensity  and  strength.  The  original 
exudation  is  very  tense,  and  after  some  time  it  changes  into 
infiltration. 

The  infiltrative  forms  are  those  in  which  the  reaction 
remains  a  long  time.  They  can  be  at  once  recognized  as  the 
form  pathologic-anatomically  described  above,  and  represent 
the  most  favourable  reaction  of  the  body  to  tubercle  bacilli 
toxins.  They  are  those  forms  which  bring  about  the  localiza- 
tion of  the  tuberculous  processes  and  prevent  the  propagation 
of   tuberculosis. 

Cunjiuictlval  Reaction. — The  conjunctival  reaction  has  so 


110  THE  OPHTHALMIC  AND  CUTANEOUS 

far  not  been  investigated  from  a  pathologic-anatomical  point 
of  view,  and  we  cannot  say,  therefore,  whether  the  changes 
m  the  vessels  and  in  the  interstitial  tissues  correspond  with 
the  cutaneous  changes,  as  is  to  be  expected.  The  investiga- 
tions carried  out  have  to  do  with  the  cytological  conditions. 
Subraxis  and  Duperie  have  discovered  mucus  and  polynuclear 
leucocytes,  and  have  demonstrated  the  absence  of  bacteria  ; 
so  also  Mongour  and  Brandeis,  who  also  mention  the  hbrin 
formations  which  mostly  occur  m  the  stronger  reactions. 
ISIobody  seems  to  mention  the  presence  of  lymphocytes  in 
the  exudations.  (Added  during  revision :  Fritz  Levy  informs 
me  verbally  that  he  has  discovered  accumulations  of  lympho- 
cytes in  the  conjunctivae  in  the  reaction  stage.) 

THE    PROGNOSTIC    SIGNIFICANCE    OP    THE    REACTION. 

Following  on  this  we  will  propound  our  theoretical  views 
concerning  the  prognostic  significance  of  the  reaction  in  so 
far  as  this  has  not  been  done  in  the  clinical  part,  to  which 
we  refer.  I  will  only  repeat  here  in  a  few  sentences  the 
principal  results  obtained  by  Stadelmann  and  myself  in  the 
clinical  investigations  we  have  carried  out  together.  Out  of 
fifteen  individuals  in  the  third  stage  of  tuberculosis  who  did  not 
react  cutaneously  (out  of  these  thirteen  did  not  react  con- 
junctivally  either),  fourteen  died  within  the  very  short  period 
of  six  weeks  ;  the  results  in  other  stages  are  even  more 
remarkable.  Of  those  in  the  second  stage  who  did  not  react 
two  died,  and  one  rapidly  passed  into  the  third  stage  ;  whilst 
from  non-reacting  individuals  in  the  first  stage  one  died,  and 
post  mortem  it  was  found  that  the  simple  reaction  had  given  a 
better  prognosis  than  the  very  thorough  clinical  investigation, 
the  autopsy  showing  that  the  clinical  diagnosis  assuming  the 
first  stage  of  the  disease  was  a  mistaken  one,  and  that  in 
reality  the  patient  was  in  the  third  stage. 

It  would  be  a  mistake  to  think  that  the  reaction  indicates 
the  pathologic-anatomical  condition  of  the  lungs.  Thus,  if 
the  reaction  is  negative,  it  does  not  mean  that  we  have  to 
do  with  a  case  of  tuberculosis  in  the  third  stage,  since  a  reac- 
tion may  be  negative  even  in  the  first  stage  of  tuberculosis. 
But  a  negative  result  indicates  that  the  body  is  no  longer 
capable  of  counteracting  the  toxins  of  the  tubercle  bacilli,  and 
therefore  has  to  be  interpreted  unfavourably  from  a  pro- 
gnostical  point  of  view.    A  positive  reaction,  on  the  other  hand, 


DIAGNOSIS    OF   TUBERCULOSIS  1  1  1 

indicates  reactive  capacity  on  the  part  of  the  body,  that  is  to 
say,  the  capacity  on  the  part  of  the  body  to  offer  resistance 
to  infection.  Whereas  a  negative  reaction  may  always  be 
regarded  as  of  unfavourable  prognosis,  the  opposite  conclusion 
may  not  be  drawn  from  a  positive  reaction.  The  positive 
reaction  indicates  that  a  battle  is  being  fought  which  as  yet 
is  undecided,  and  tlje  result  of  which  cannot  yet  be  foreseen. 
He  who  would  base  a  favourable  prognosis  on  the  result  of 
the  reaction  would  make  the  mistake  of  resardincr  battle  and 
victory  as  synonymous. 

These  remarks  will  explain  why  sometimes  in  very  advanced 
cases  the  reaction  is  positive.  Experience  has  taught  me  that 
these  are  the  cases  in  which  many  years  of  a  diseased  condition 
have  produced  great  pulmonary  changes,  despite  which,  death 
is  still  far  off. 

These  important  diagnostic  and  prognostic  conclusions  may 
be  gained  by  simply  observing  the  course  of  the  reaction 
during  four  consecutive  days.  Stadelmann,  who  is  well 
known  as  a  careful  and  critical  clinician,  has  definitely  fallen 
in  with  the  prognostic  conclusions  the  reaction  enables  us 
to  draw,  and  he  attaches  an  even  greater  significance  to  the 
prognostic  than  to  the  diagnostic  value  of  the  reaction. 
These  observations  would  be  sufficient  to  regard  the  expecta- 
tions I  expressed  on  May  15,  1907,  at  the  Berliner  medizinische 
Gesellschaft,  as  fulfilled.  But  I  was  not  content  with  the 
results.  I  was  of  opinion  that  the  results  thus  far  obtained 
merely  represented  the  foundations  of  a  structure,  the  develop- 
ment of  which  in  time  would  prove  of  the  very  greatest  value. 
So  far,  only  the  crudest  diagnostic  means  had  been  employed, 
and  the  quantitative  differences  of  sensibility  to  different  con- 
centrations, already  fully  demonstrated  by  Pirquet  and  myself, 
had  hardly  been  considered.  8o  as  not  to  complicate  matters 
too  much  in  the  investigation  of  great  numbers,  we  did  not 
take  into  consideration  that  distinct  differences  are  found 
in  each  particular  case  according  to  the  preparation  of  tubercle 
bacilli  employed  ;  old  tubercuHn,  fresh  tuberculin,  tuberculol, 
emulsion  of  bacilli,  tuberculin  fi'om  tuberculous  oxen,  S:c., 
all  produced  different  results,  and  their  observation  and  appli- 
cation promises  further  diagnostic  and  prognostic  success. 
(See  the  chapter  on  the  differences  of  tuberculin  reactions.) 
The  prognostic  significance  of  the  reaction  seemed  to  me 
to  be  the  most  important,  and  starting  from  the  principle  that 
a  representation  of  the  course  of  the  reaction   by  curves  would 


112  THE  OPHTHALMIC  AND  CUTANEOUS 

lead  to  important  and  decisive  discoveries  along  this  line,  I 
made  a  careful  study,  in  co-operation  with  my  colleague,  Mr. 
Teichmann,  assistant  of  the  hospital  in  Friedrichshain,  of  the 
reaction  as  represented  by  most  accurately  drawn  curves,  com- 
paring the  results  obtained  with  clinically  investigated  cases, 
and  I  believe  we  have  succeeded  in  obtaining  excellent  evidence 
in  favour  of  the  prognostic  significance  of  the  reaction. 

THE    PROGNOSTIC    SIGNIFICANCE    OF    THE    CUTANEOUS    AND 
CONJUNCTIVAL    REACTIONS. 

The  following  observations  were  made  when  Koch's  old 
tuberculin  (tested  by  order  of  the  State  by  the  Kuete- 
Enoch  method)  was  used  in  a  1  per  cent,  solution  for  the 
conjunctival  reaction,  and  in  a  25  per  cent,  solution  for  the 
cutaneous  reaction.  In  order  to  obtain  results  of  prognostic 
value  and  which  may  be  compared,  it  is  not  only  essential  to 
employ  the  same  concentration,  but  also  to  use  tubercuhn 
of  the  same  origin,  and  we  advise  the  ordering  of  a  large 
amount  of  tuberculin  at  one  time,  because  even  if  the  origin 
of  preparations  be  the  same  there  may  easily  be  some  differ- 
ence in  the  power  of  action  in  tuberculin  of  different  consign- 
ments. The  fact  that  the  reaction  depends  on  the  degree  of 
concentration  of  the  solution  employed  shows  that  there  is 
a  difference  in  the  influence  of  solutions  containing  different 
amounts  of  tuberculin,  although  Pirquet  may  not  be  quite 
correct  in  assuming  that  the  strength  of  the  action  is  pro- 
portionate to  the  strength  of  the  solution  employed.  (See 
Curve  fig.  No.  1,  p.  114.)  The  differences,  however,  are 
only  of  the  intensity  of  reactions,  and  do  not  refer  to  the 
course  of  the  curve.  Now  from  our  observations  it  is 
clear  that  the  form  taken  by  the  diseases  typically  condi- 
tions the  law  governing  the  course  of  the  reaction.  In 
order  to  allow  the  judgment  concerning  the  course  of  the 
reaction  to  be  entirely  independent  of  the  subjective  obser- 
vation of  the  investigator,  and  also  to  make  the  results 
very  plain,  I  and  my  colleague  Teichmann  have  drawn  up 
a  scheme  which  served  us  in  drawing  up  the  curve  figures 
(see  the  curve  tables). 

As  a  rule  the  reaction  was  applied  in  the  morning",  so  as  to 
enable  us  to  make  observations  six  or  seven  tnnes  in  the  course 
of  the  day,  and  also  in  order  not  to  overlook  the  rapidly 
fading  type   of  reaction,    as    once   occurred.      The  pomphous, 


DIAGNOSIS    OF    TUBERCULOSIS  113 

or  papule,  which  came  up  was  measured  by  means  of  a  tape 
measure,  measuring  the  infiltration  and  the  reddish  halo 
separately,  since  they  can  almost  always  be  separated.  The 
curves  representing  the  infiltration  are  as  a  rule  homologous, 
•^-nd  the  separate  measuring  has  the  advantage  that  artificial 
irritation,  such  as  is  produced  by  scratching,  can  easily  be 
distinguished  from  the  curves  themselves.  For  the  rest  the 
infiltration  during  the  first  few  days  consists  of  a  strong 
exudation  which,  if  palpated  by  the  finger,  gives  almost  the 
same  impression  as  an  infiltration  proper.  Despite  all  our 
experiments  in  this  direction  we  have  not  been  able  to 
clinically  differentiate  between  infiltrative  and  exudative  pro- 
cesses. This  can  only  be  done  by  means  of  the  pathologic- 
anatomical  investigation. 

The  length  of  the  pomphus  is  then  registered  on  the 
ordinate  of  the  curve,  whilst  the  abscissa  indicates  the  time 
which  has  elapsed  after  the  application  of  the  reaction. 

It  is  more  difficult  to  represent  by  a  curve  the  course  of 
the  conjunctival  reaction,  since  its  values  cannot  be  expressed 
numerically.  But  the  use  of  the  indications  "trace,"  "first 
degree,"  "  second  degree,"  and  "  third  degree "  of  the  re- 
action suffices  to  represent  the  course  of  the  conjunctival 
reaction. 

The  curve  figures,  Nos.  1  to  11,  refer  to  typical  cases 
chosen  according  to  clinical  indications.  To  prevent  miscon- 
ceptions I  will  lay  special  stress  on  the  fact  that  they  do 
not  represent  cases  that  have  come  under  observation  in  a 
haphazard  way.  On  the  contrary,  they  show  by  exact 
curves  what  could  only  be  expected  after  the  investigations 
Professor  Stadelmann  and  myself  were  carrying  out ;  they 
prove  to  a  most  exact  degree  the  correctness  of  the  funda- 
mental principles  deduced  from  our  investigations  of  great 
numbers  as  dealt  with  in  the  Clinical  Part,  and  which  refer 
to  the  local  application  of  tuberculin  reaction. 

The  following  types  of  curves  are  to  be  recognized  : — 

I.  The  normal  type,  representing  the  specific  normal 
reaction  of  patients  infected  with  tuberculosis. — This  is  a  vivid 
reaction  which  fairly  quickly  appears.  It  becomes  apparent 
four  to  six  hours  after  the  application  of  the  reaction,  and 
reaches  its  maximum  after  twenty  to  twenty-four  hours.  This 
maximum  remains  at  the  same  level  on  the  second  day  and 
pales  down  in  the  course  of  the  third,  or,  at  the  latest,  during 
the  fourth  day.  In  the  place  of  the  pomphus  there  remains 
8 


114  THE  OPHTHALMIC  AND  CUTANEOUS 

a  slight  pigment  stain  of  the  same  size  for  one  to  two  weeks, 

which  then  absolutely  disappears.     One   may  in  this  normal 

type  still  distinguish  between  a  strong  course  and  a  medium 

strong  course,  which  may  become  clear  from  the  curve  tables. 

Curve,  fig.  1  :  strong  reaction.  )  ,,  .,-,  , 

.  .       '-  See  p.  114. 

Curve,  fig.  2  :  medium  strong  reaction.]         ^" 

As  above  mentioned,  this  normal  type  is  the  type  of  the 
specific  normal  reaction.  This  course  is  found  in  the  great 
majority  of  cases  of  initial  tuberculosis,  and  also  in  those  cases 
of  the  first  and  second  stage  which  show  a  favourable,  that 
is  to  say  a  slow,  progress. 

There  are  two  departures  from  this  normal  type  •  — 

(1)  The  rapid  hut  very  weak  and  ephemeral  7-eaction  in  the 
case  of  manifest  tuberculosis,  which  is  frequently  overlooked, 
and  (2)  the  late  or  lasting  reaction.  A  special  clinical  sig- 
nificance is  to  be  attached  to  both  these  forms.  We  will  first 
deal  with  the  weak  and  ephemeral  rapid  reaction  of  manifestly 
tuberculous  cases. 

This  reaction  is  distinguished  by  its  rapid  course  and  its 
very  superficial  nature.  Like  the  normal  type,  it  already 
appears  six  hours  after  the  application  of  the  reaction  ;  it 
soon  reaches  its  maximum  point,  sometimes  as  early  as  ten 
hours  after  application,  and  it  disappears  just  as  quickly,  at 
the  latest  in  the  course  of  the  second  day.  It  does  not  leave 
any  traces  behind. 

This  reaction  frequently  takes  a  course  so  rapid,  and  its 
intensity,  even  at  its  maximum,  is  so  slight,  that  it  is  very 
often  overlooked,  unless,  indeed,  the  observations  are  made 
every  two  hours.  We  are  sure  that  in  our  clinical  observa- 
tion of  great  numbers,  in  which  the  result  of  the  reaction  was 
taken  up  after  twenty  to  twenty  four  hours,  it  has  been  over- 
looked, since  after  twenty-four  hours  nothing  is  left  of  it.  (This 
form  of  reaction  is  frequently  found  in  cases  of  tuberculosis  of 
the  third  stage,  more  rarely  in  those  of  the  first  and  second 
stages  of  pulmonary  tuberculosis,  that  is  to  say,  in  those  cases 
which  are  distinguished  by  a  specially  unfavourable  course  of 
the  reaction).     (See  curve  figures  3,  4  and  b,  p.  116.) 

Such  a  form  of  reaction,  therefore,  indicates  (as  is  evident 
from  these  remarks)  an  unfavourable  prognosis,  viz.,  a  rapid 
course  of  the  tuberculosis.  If  the  reaction  is  altogether  absent 
the  chances  are  even  more  unfavourable,  and  this  has  only 
been  noticed  in  patients  who  died  within  a  short  period  of 
time. 


Curve  Table  I. 


rst  Stage. 


J'oAn  Bale,  Son:  &'  Danielssor 

,  Ltd., 

London. 

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t 

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S   JO    12  1¥     ie  IS    20  22   2¥2. 
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II.  Day  III.  Day.  IV.  Day. 

_o  — o  — o—    Infiltration  4     upper  25°/o      ,         ,. 
-"->-—    Reddening)     lower  1  o/J     ^^ercuUn. 

Wolff-Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


K        VI      VII       VIII       IX.     X.  Day. 

Taken  in  October  and  8t>'  December  1907, 
Curve  of  St^-  December  '07. 

Dismissed  in  good  condition  after 
favourable  local  appearances. 


¥Q 

Tuberculosis. 

John 

Curve  Table  II. 

Bale,  Sons  &•  Daniehson,  Ltd.,  London. 

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Curve  Table  II. 


Conjunctival  and  Cutaneous  Reactions  in  a  case  of  Early  Tuberculosis. 


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I.  Day 


Specific  normal  reaction. 


°— o—     Infiltration 
"    ^~     Reddening 


Wo  Iff- Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


V.        VI.      Vn.      VIIL      JX.     X.  Day. 


Taken  on  8'''  Dec.  '07. 
20'i'  Jan.  '08:  condition  very  satisfactory. 


DIAGNOSIS    OF   TUBERCULOSIS  115 

The  fact  that  in  the  case  of  oi'dinary  ohservation  after 
twenty-four  hours  the  rapid  and  superficial  reaction  may  be 
overlooked  is  not  of  very  great  importance  for  all  practical 
purposes,  since  this  form  of  reaction  indicates,  like  the  fully 
negative  reaction,  an  unfavourable  prognosis,  and  the  mistake 
may  safely  be  regarded  as  nil.  For  scientific  purposes, 
however,  these  conditions  have  to  be  taken  into  account. 

The  second  departure  from  the  normal  type,  the  late 
reaction  (or  rather  the  late  and  lasting  reaction),  has  an 
exactly  opposite  clinical  significance.  Its  course  is  as  follows  : 
The  first  evidence  of  the  reaction  occurs  after  about  the 
same  space  of  time  as  in  the  case  of  the  others  ;  the  maxi- 
mum point,  however ,  is  not  reached  quickly,  but  only  very 
gradually,  at  the  end  of  the  second  day,  or  even  later.  In 
sharp  contrast  to  the  quick  reaction  of  the  manifestly  tuber- 
culous cases,  it  remains  unchanged  for  days  at  its  maximum 
point,  on  an  average  persisting  like  that  for  a  whole  week. 
But  it  has  sometimes  been  found  unchanged  even  after  three 
and  more  weeks.  This  course  of  the  reaction  is  illustrated 
by  curve  figures  6,  7,  8  and  9  on  p.  118. 

This  type  of  curve  is  of  profound  diagnostic  significance. 
This  reaction  is  only  found  in  those  cases  in  which  clinically 
there  are  no  indications  whatever  of  active  tuberculosis.  We 
may  maintain  with  practically  absolute  certainty  that  the  late 
reaction  represents  the  type  of  reaction  of  cases  of  perfectly 
inactive  tuberculosis.^ 

The  prognostic  conclusions  drawn  from  the  course  of  the 
reaction,  therefore,  may  be  synthesized  as  follows  :  If  a  patient 
loith  initial  tuberculosis  reacts  according  to  the  normal  type, 
toe  7nay  make  a  favourable  prognosis,  increasing  in  propitious- 
ness  icith  the  strength  of  the  reaction  within  the  limits  of  this 
normal  type.  Weak  rapid  reactions,  or  even  altogether  nega- 
tive ones,  point  to  an  unfavourable  course  of  the  disease. 

Strong  reactions  according  to  the  normal  type,  in  ana- 
tomically advanced  cases,  indicate  a  certain  healing  tendency, 
and  therefore  signify  stasis  or  slow  progression.  In  advanced 
cases  a  rapid  reaction  indicates  quick  intensification  of  the 
disease  ;  no  reaction  predicts  an  early  death. 


'  On  this  point  I  differ  from  Stadehnann,  who  regards  the  late  reaction 
as  that  of  healthy  individuals,  whereas  I  regard  it  merely  as  that  of  clinic- 
all  y  healthy  persons.  From  a  practical  point  of  view  the  diflerence  is  of 
no  great  importance :  tlie  theoretical  reasons  for  my  opinion  are  expounded 
in  various  places. 


116  THE  OPHTHALMIC  AND  CUTANEOUS 

It  may  be  objected  to  our  view  of  the  matter  that  it  is 
very  remarkable  that  the  majority  of  initial  cases  should  give 
a  strong  reaction,  and  that,  on  the  other  hand,  most  of  the 
advanced  cases  give  an  altogether  negative  reaction  or  one 
of  but  slight  intensity.  If  we  think  the  matter  over,  this 
frequent  correspondence  with  the  anatomical  condition  will 
not  appear  so  strange.  Tuberculosis  is  an  infectious  disease, 
which  leads  to  death  within  a  short  time  if  the  body  offers  no 
resistance  (miliary  tuberculosis).  The  great  majority  of  cases 
in  which  the  apex  is  affected  do  not  show  a  rapid  course, 
but  one  stretching  over  years,  and  this  resisting  capacity 
in  affections  of  the  apex  is  shown  by  the  reaction  of  the 
normal  type.  In  pulmonary  tuberculosis  of  the  third  stage 
the  resisting  capacity  of  the  body  very  frequently  is  exhausted 
— as  may  be  judged  by  purel}'  clinical  means — and  as  an 
exterior  sign  of  their  condition  these  persons  respond  nega- 
tively to  the  reaction,  or  give  a  rapid  reaction.  But  this  can 
be  said  with  absolute  certainty  :  the  form  the  reaction  takes 
is  not  in  any  way  connected  with  the  anatomical  character  of 
the  lesion,  and  it  is  just  those  cases  which  anatomically  deviate 
from  the  expected  type  of  reaction  that  are  clinically  of  the 
greatest  interest.  And  the  observation  of  such  cases  has 
shown  that  our  method  of  prognosis,  based  on  the  reaction, 
is  of  great  value. 

I  wish  to  call  special  attention  to  one  point.  The  strong- 
normal  reaction  in  cases  of  tuberculosis  does  not,  of  course,  in 
itself  guarantee  a  favourable  course  of  the  disease,  and  cannot 
definitely  indicate  the  further  course.  It  only  shows  that  at 
the  time  at  which  the  reaction  is  applied  the  body  is  still  in 
full  possession  of  all  its  bodily  energy,  combating  the  infec- 
tion. Combat  indicates  the  possibility  of  victory,  not  victory 
itself.  And  this  capacity  to  react  shows  that  in  such  a  case 
the  donning  of  the  whole  of  our  therapeutic  armour  may  not 
be  in  vain.  The  limitation  referred  to  lies  in  the  nature  of 
the  case  :  it  would  be  an  exaggeration  (and  every  able  medical 
man  would  think  it  improbable)  to  say  that  any  reaction  would 
definitely  indicate  a  favourable  course  of  the  disease,  especially 
since  we  know  the  influence  of  external  measures  on  the  course 
of  tuberculosis.  Moreover,  if  this  were  the  case,  the  whole 
of  the  importance  of  the  dietetic  therapy  would  fall  away,  and 
this  would  certainly  not  be  a  progressive,  but  rather  a  retro- 
gressive step  in  combating  tuberculosis. 

But  even  within  this  limitation,  inherent  in  the  nature  of 


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Conjunctival  and  Cutaneous  Reaction  in  a  case  of  Tuberculosis  in  the  Second  Stage. 

According  to  ^olff-Eisner  and  Teichmann.  5'oA"  BaU.  s<m 


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—  o — o — .o~    Infiltration 
/ith  uniavourable  prognosis.  -»— «— x-    Reddening 

Wolff- Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


K        (••/.      V/l.       VIII.       IX.     .V.  Da,: 


Taken  on  22""i  Dec.  1907. 
Died  on  13*  Jan.  '08. 


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Mdller.     Dementia  alcoholica.  Bronchitis.    Tbc.       Type  II  (Rapid  reaction  with  unfavourable  prognosis). 

Wolff- Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


V.        VI.      VU.       VIII.       IX.     X.  Day. 


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_o— o— o—    Infiltration 
Murzyn,    Stage  II.  Type  II  (rapid  reaction  with  unfavourable  prognosis).     —* — ^ — >« —    Reddening 


V.        VI.      VII.      VIIL      IX,     X.  Day 


Curve  of  Dec.  4.  1907  (minimal  lung  appearances  subfebrile). 
Followed  fay  hectic  fever;  very  bad  prognosis. 


Wolff- Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


DIAGNOSIS    OF    TUBERCULOSIS  117 

the  progress  of  an  infectious  disease,  the  importance  of  the 
fact  that  our  analysis  of  the  reaction  enables  us  to  make  a 
prognosis  based  on  biological  changes  needs  no  elaboration. 

These  important  practical  results  of  the  prognostic  signi- 
ficance of  the  reaction  are  in  need  of  a  theoretical  founda- 
tion. We  will  at  once  proceed  to  discuss  such  a  foundation 
in  accordance  with  modern  views,  especially  with  a  view 
of  explaining  the  principles  underlying  the  reaction  to  the 
clinician.  The  complicated  theoretical  problems  which  in 
their  turn  spring  up  on  the  basis  of  such  an  attempt,  and  to 
which  an  answer  has  been  found,  will  be  dealt  with  in  the 
course  of  this  explanation. 

According  to  the  prevailing  view,  introduced  into  science 
and  practice  by  Wassermann,  the  tuberculin  reaction  depends 
on  the  combination  of  the  anti-tuberculin  substances  which 
are  present  in  the  bodies  of  the  tuberculous  affected,  against 
the  tuberculin  introduced.  According  to  this  theory,  there- 
fore, one  might  expect  the  reaction  in  the  skin  and  on  the 
conjunctiva  to  be  most  distinct  and  strongest  in  those 
cases  in  which  the  body  is  still  in  full  possession  of  its 
defences  :  that  is  to  say,  in  which  the  body  is  best  able  to 
produce  the  assumed  anti-tuberculin  substances,  therefore  in 
the  majority  of  incipient,  and  in  those  of  the  more  ad- 
vanced cases  in  which  the  body  may  successfully  offer  resis- 
tance to  the  progress  of  the  infection. 

If  one  assumes  that  with  the  piogress  of  the  process  of 
infection  the  resisting  capacity  of  the  body  decreases,  and 
that  the  resisting  substances  are  no  longer  produced,  one 
can  understand  why  the  reaction  should  become  weaker  in 
the  progressing  cases  and  in  those  which  take  an  unfavour- 
able course,  until  finally  the  body  of  the  consumptive,  which 
is  altogether  incapable  of  reaction  and  severely  cachectic,  in 
the  final  stage  cannot  possibly  respond  to  the  irritation  pro- 
duced under  ordinary  circumstances  by  a  '25  per  cent, 
tuberculin  solution. 

It  cannot  be  denied  that  these  extremely  simple  theoretical 
explanations  of  the  course  of  the  reaction  would  satisfy  both 
the  practitioner  and  the  theoretical  scientist  to  the  same 
extent.  However,  more  precise  analysis  has  shown  that  highly 
complicated  processes  take  part  in  the  origination  of  the 
reaction,  and  although  this  complication  of  apparently  simple 
conditions  is  to  be  regretted,  yet  a  simplification  is  introduced 
by  this  very  fact,  showing  that  the  tubercle  bacillus  no  longer 


118  THE  OPHTHALMIC  AND  CUTANEOUS 

occupies  a  peculiar  position,  but  t,akes  its  natural  place  with 
reference  to  the  great  biological  law  governing  the  intro- 
duction of  foreign  albuminoid  substances. 

THEOKETICAL    PART    OF    THE    PROGNOSTIC    SIGNIFICANCE    OF 
THE    REACTION. 

In  order  to  explain  these  conditions  we  shall  have  to  go 
back  a  little  further,  to  the  question  relating  to  the  specific 
nature  of  the  reaction.  Everyone  will,  of  course,  be  some- 
what startled  by  the  statement  that  a  number  of  manifestly 
tuberculous  individuals  do  not  respond  to  either  a  cutaneous 
or  conjunctival  reaction  (or  rather,  as  shown  above,  give  so 
rapid  and  ephemeral  a  reaction  that  it  can  easily  be  over- 
looked). One  is  very  apt  to  conclude  (especially  if  one  dis- 
regards our  latest  discoveries)  that  for  this  reason  the  reaction 
cannot  he  specific. 

Clinically  speaking,  this  absence  of  the  reaction  is  no 
disadvantage.  That  the  reaction  really  has  a  prognostic 
significance  is  shown  by  the  fact  that,  as  mentioned  above, 
a  clinician  like  Stadelmann  accepts  this  view,  and  defends 
it  with  great  enthusiasm.  The  prognostic  significance  of  the 
reaction  cannot  any  longer  be  disregarded  to  the  same  extent 
as  was  the  case  after  I  first  communicated  it ;  it  will  become 
as  generally  recognised  as  the  diagnostic. 

Thus  it  has  been  proved  that  the  absence  of  the  reaction 
is  of  advantage  for  clinical  purposes  ;  this  fact,  however, 
cannot  fully  do  away  with  all  doubt  as  to  its  specific  nature. 
In  this  connection  it  must  be  mentioned  that  also  the  sub- 
cutaneously  injected  tuberculin  does  not  produce  a  reaction  in 
advanced  cases.  The  question  concerning  the  specific  nature 
of  the  reaction,  therefore,  is  identical  with  the  question  as  to 
the  specific  nature  of  tuberculin  itself.  And  that  tuberculin 
has  a  specific  action  has  been  proved  by  numerous  experi- 
ments, so  that  it  is  hardly  necessary  to  further  discuss  this 
problem  here. 

To  this  is  added  that  our  investigations  have  shown  that 
progressive  tuberculosis  does  not  give  an  altogether  negative 
reaction,  but  that  the  reaction  is  of  another  type,  a  rapid  type, 
and  that  it  is  only  absolutely  absent  in  cases  of  very  severe 
cachexia  and  in  the  last  days  of  life. 

We  have  already  made  reference  to  the  Wassermann 
theory,  which  is  the  one  that  has  found  the  widest  acceptance 


DIAGNOSIS    OF    TUBERCULOSIS  119 

amongst  practitioners,  maintaining  that  the  tubercuhn 
reaction  is  brought  about  when  tuberculin  encounters  anti- 
tubercuhn.  The  meeting  of  both  substances  in  the  tuber- 
culous centre  causes  the  reaction.  The  fact  that  the  reaction 
does  not  appear  after  the  application  of  tuberculin  may  be 
explained  by  the  fact  that  anti-tuberculin  freely  circulates  in 
the  blood,  where  it  already  meets  the  injected  tuberculin. 
The  tuberculous  centre  is  to  some  extent  surrounded  by  the 
anti-tuberculin  circulating  in  the  serum,  so  that  no  tuberculin 
can  enter  it. 

It  is  very  interesting  to  know  that  some  time  ago  Pirquet 
maintained  a  similar  theory  with  regard  to  serum  disease, 
which  now'  he  has  accepted  with  reference  to  the  tuberculin 
reaction.  The  reaction  in  this  case,  the  serum  disease,  is 
brought  about  by  the  fact  that  the  albumin  encounters  its 
anti-substance  in  the  skin,  and  here  it  produces  the  symptoms 
of  the  disease.  It  has  always  seemed  to  me  that  this  theory 
was  improbable  in  several  respects  ;  I  could  not  believe  that 
toxin  meeting  with  an  antitoxin  could  produce  a  reaction. 
My  experiments  rather  pointed  to  the  probability  that  the 
difference  between  the  clinical  phenomena  in  the  repeated 
injection  and  those  in  the  first  injection  is  due  to  the 
changed  conditions  of  absorption.  In  this  way  I  regarded  the 
foreign  albuminoid  substances  as  analogous  to  the  bacterial 
albumin,  and  the  bacteriolysine,  which  appeared  after  intro- 
ducing bacterial  albumin,  I  regarded  as  analogous  to  the 
processes  appearing  after  the  introduction  of  albumin,  and 
in  this  way  I  formed  the  theory  of  the  alhuminolysincB,  which 
assumes  that,  under  the  influence  of  the  first  introduction  of 
albuminoid  substances  into  the  body,  reaction  substances  are 
formed  which  destroy  the  albumin  in  a  way  analogous  to  the 
bacteriolysines,  changing  the  conditions  of  absorption  and 
liberating  poisonous  (endotoxin)  substances  from  the  albumen. 
(See  A.  Wolff-Eisner,  Zentr.f.  Bakter.,  vol.  40,  No.  3.) 

These  explanations  are  not  irrelevant  to  the  subject, 
because  the  same  problems  have  to  be  discussed  in  regard  to 
the  action  of  tuberculin.  In  reference  to  the  Wassermann 
theory  I  must  mention  that,  despite  many  experiments,  I  have 
never  succeeded  in  finding  an  anti-tuberculin  in  the  sense  of 
a  substance  which  is  capable  of  neutralizing  tuberculin.  The 
theory  concerning  the  existence  of  anti-tuberculin  as  accepted 
by  Wassermann  is  known  to  be  based  on  the  assumption  that 
tuberculin  is  capable  of  forming  a  complement  in  unison  with 


120  THE  OPHTHALMIC  AND  CUTANEOUS 

anti-tuberculin  ;   thus,  indirectly,   it  was  concluded  that  anti- 
tuberculin  was  present. 

Now  our  investigations  enable  us  to  fully  maintain  my 
former  view  of  the  question  concerning  the  action  of  tuber- 
culin, or  rather  to  adopt  it  without  alteration  with  reference 
to  the  tuberculin  reactions,  and  yet  to  fully  explain  all  observa- 
tions made  by  Wassermann  which  in  the  first  instance  led 
to  the  doctrine  of  anti-tuberculin.  Notwithstanding  the  fact 
that  our  investigations  compel  us  to  modify  the  theory  con- 
cerning the  action  of  tuberculin,  we  must  acknowledge  that 
Wassermann,  in  his  excellent  experiments  and  their  ingenious 
interpretation,  was  on  the  right  way  and  has  made  it  possible 
for  us  to  attempt  a  solution  of  these  complicated  processes. 

I  have  the  impression  that  the  toxin  theory  in  the  science 
of  tuberculosis,  as  also  in  that  of  other  infectious  diseases,  has 
given  rise  to  numerous  diagnostic  and  theoretical  misconcep- 
tions.^ Especially  in  dermatology  a  voluminous  discussion 
has  arisen  around  the  question  whether  certain  affections  of 
the  skin  are  due  to  the  tubercle  bacillus  or  to  toxins  secreted 
by  tubercle  bacilli.  All  these  discussions  will  prove  to  have 
been  fruitless  if  our  discoveries  be  confirmed.  These  show 
that  the  action  of  tuberculin  is  due  to  the  particles  of 
tubercle  bacilli  ;  in  fact,  that  tuberculin  only  consists  of  very 
minute  particles  of  tubercle  bacilli.  Tuberculin  represents 
the  type  of  preservable  endotoxin.  The  endotoxin  doctrine 
becomes  more  and  more  accepted  in  clinical  science,  and 
the  times  have  passed  in  which  the  word  "endotoxin"  was  not 
very  pleasant  to  hear,  because  now  our  knowledge  concerning 
bacterial  and  albuminoid  poisons  enables  us  to  clear  up  many 
dark  problems,  whilst  at  the  same  time  this  doctrine  con- 
cerning the  indications  for  treatment  affords  a  basis  in  the 
case  of  the  bacteriocide  serum  therapy.  In  the  case  of  tuber- 
culin our  curve  figures  prove  that  we  have  to  do  with  the 
action  of  dissolving  substances.  A  coincidence  however, 
afforded  a  direct  proof  that  we  have  simply  to  do  with 
bacteriolysine. 

It  is  a  well-known  fact  that  in  times  gone  by  tuberculin 
contained  great  masses  of  tubercle  bacilli.  Most  of  the 
manufacturers  of  the  present  day,  however,  filter  the  tuber- 
culin through  Chamberland  or  Berkefeld  candles,  and  in  these 
cases  we  may  regard  as  excluded  the  probability  that  tubercle 

1  See  A.  Wolff-Eisner,  Berl  klin.  Wochenschr.,  1907,  No.  38. 


lealthy 

individual 

. 

Curve  Table  VI. 

^oAn  Bale,  Sons  &*  Daniehson,  Ltd.,  London. 

: .  -l.  - 

-■         - 

~        - 

;           '           '                      '           ■            ' 

•           1           '           '           1           :           f         ■           i 

1    1 

_ !_  ^_  _;_  _,'  _____!_ 

1      i      1      '      !      ' 

1      1            1      ;      1 



I    1    1    1    1    ^    ,    1 

! 

T 

;         j 

1 
1         ,         j 

1        1 

1 

1       ' 

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1    ; 

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1    1 

1 

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-I '  - 

1 

— ' — i — 1 — i — I — 

i    i    i 

1     ; 
1     1 

1    '    1 



-         - 

!   1 

l~^ 

i          1 

!    1    1 

1 

i 

t-i-n 

1 

i 



!      ' 

!       1 

i      i      ' 

; 
1 
1 



i 

1    H  ,  - 
■ 

i 

1 

Li      ^J 

1 

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1 

i 





!             i 
1     ]            1 

1 

fr'"T"^—h"f"i 

.... 

.... 

— 



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i     !     i     !     i 

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i 

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n 
'ubercul 

osij 

Day 
i. 

V. 

VI      I 

^11    I 

VII 

IX.     ,^ 

'.  Day. 

Curve  Table  VI. 


Cutaneous  Reaction  with  25%  Tuberculin  in  a  clinically  healthy  individual. 


Accor 

iing 

to 

Wolff-Eisner  a 

nd 

Tet 

chn 

an 

n. 

John  B 

tU.  S<m 

•  b-  Da 

nUt»,n 

Lid..  L 

a.im. 

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,    ,    ,    1    1    '    1    ,    1 

V.        VI.      VII.      VIII      IX.     X.  Day. 


Type  III.   (lasting  reaction). 


Wolff- Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


ials. 

Curve  Table  VII. 

John  Bale,  Sons  &-  Daniehson,  Ltd.,  Ivndon. 

fO 

( 

--- 

—  - 

"- 

^ 





39 

< 

\_ 

i 

^38 



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36 

i 

1' 

r 

3 

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t 

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1 

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o~«~o~ 

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^. ^. 

p«// 

*"'Ss 

i 

i 

en 

/ 
:ulo 

sis. 

Day 

V. 

VI.      I 

///.     I 

^III. 

IX.     J\ 

r.  Day. 

Curve  Table  VII. 


Wolff-Eisner  and  Ttichm 

.„„ 

Cutaneous 

Reactior 

in 

clinically  healthy 

individuals 

>*.  a 

cU.S^ 

•  &-i>.. 

..itan. 

i(rf.,  / 

mJn. 

---- 

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1 

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e   aw   12  n   fs  , 

I.   Day 


21  Zt    Hears 


III.  Day 


V.        VI.     VII.      VIII.      IX.     X.  Dav. 


Szagum  (lysol  poisoning),    (unsuspected.) 


n.  Cutaneous  inoculation.    !■'  —  5*  day.    Type  III.  (Lasting  reaction). 

(I,  Tr..  I,  I,  I.) 

W  o  I  f  f -  £  i  s  n  e  r,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


lals 

• 

Curve  Table  VHI. 

yoin  Bale,  Sons  &-  DanieUson,  Ltd.,  London. 

■ 

.. 

3i 

1 

1 

.  p-|-- 

^ 

1 

«* 

1 

^^ 

a 

K 

.. 

1' 

1  J 

8* 

. 

. 

ro^ 

c 

?" 

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^ 

J 

^ 

S  ST 

5;  ^ 

^  * 

i^ 

i 

b 

. 

V 

-o— 

o— 

o— 

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D— 

D— 

oH 

o— 

j7 

•  '^ 

cv 

> 

n 
culo 

sis. 

^ay. 

V. 
Dismis 

VI. 
sed  w 

VII. 
ithout 

nil 

clinica 

IX.     } 
1  sym 

Sr.  Day. 
ptoms. 

Curve  Table  VIII. 


Cutaneous  Reaction  in  clinically  healthy  individuals. 


Wolff-Eisner 

an 

i  Teichmann 

3,h„B 

oU.  Son 

I  fr  D« 

„>to„ 

i(,<.,  LmJm. 

»" 

-. 

^" 

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. 

1 

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la?" 

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r 

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1 

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ni 

(0 

; 

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) 

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(0) 

tii^ 

COJ 

f    ■     ' 

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ft 

6 

% 

SB 

* 

t 

.s* 



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- 



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tz 

nf; 

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t>— 

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^ 



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. 

Z     ¥     6    8    10     iZ  n 
I.   Day 


Mittag,  Neurasthe 


//.   Day 
Late  and  lasting  reaction. 

Wolff-Ei 


V.         VI.      VII.       VIII.       IX.     X.   Day. 
Dismissed  without  clinical  symptoms. 


r,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculoas. 


*st 

Stage. 

Join  BaUy  Son 

Curve  Table  IX. 

J  b'  Daniehson,  Ltd.,  London. 

H 

.... 

— - 

.._J.... 

1 

—  - 

M 

1 

I- 

! 

-- 

--- 

-- 

-- 



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b.  ;x: 

1    [ 

■" 

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s 

1 

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t 

si 

1 

1 

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c 

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^x- 

-X. 

-x^ 

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\--^ 

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1 

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1 

n 

:ul< 

^.  1 

>sis 

V. 

. 

E 

:nd 

of 

Jar 

V. 

Cur 
1.  '08  1 

VI.      / 

ve  of 
ew  lo 
no 

ni.        I 

10*  D 
cal  ap] 
sputun 

^III. 

ec.  19 
aearan 
1. 

IX.     X 

37. 
ces,  su 

'.   Day. 

bfebri] 

Curve  Table  IX. 


Cutaneous  Reaction  in  a  case  of  Tuberculosis  in  the  First  Stage. 


Wolff- 

Eisner  and  Teichmann 

JoMnS 

aU.  Sm 

t  fs-  Da 

„Vto. 

UJ.,  Lmd„n. 

'     i 

-i 

-i- 

.._!,_. 

■  -  j  - 

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-' 

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L--I--J.  -4  - 
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»     «  »     16   M     iO  ZZ   Zf  Jfom-S 
I.  Day 


c  li  t.    Stage  I.  Specific  normal 


//.   Day  in.   Day. 

going  over  into  a  lasting  reaction. 

Wolff- Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


V.        V!.      VII.       VIII.       IX.     .V.   Day. 

Curve  of  10'l>  Dec.  1907. 

End  of  Jan.  '08  few  local  appearances,  subfebrile, 

no  sputum. 


DIAGNOSIS    OF    TUBERCULOSIS  121 

bacilli  are  to  be  found  microscopically  in  the  tuberculin, 
except  in  the  case  that  some  filter  or  other  had  been  some- 
what defective.  The  Kuete-Enoch  tubercuhn  which  we 
employed  has,  according  to  the  assurances  of  the  manu- 
facturer, only  been  filtered  through  paper  filters,  and  after 
having  centrifuged  the  product  in  my  own  laboratory  Daels 
discovered  a  great  many  tubercle  bacilli  and  particles  of 
tubercle  bacilh.     {Med.  KL,  1908,  No.  2.) 

Now  the  theoretical  importance  attached  to  this  discovery 
lies  in  the  fact  that  this  tuberculin  has  been  tested,  by  order 
of  the  Prussian  Government,  at  the  Institute  for  Experi- 
mental Therapy  at  Frankfort  a.  M.,  and  for  this  reason  is 
identical  in  action  with  the  other  kinds  of  tuberculin.  When, 
subsequently,  our  tuberculin  was  passed  through  the  Berke- 
feld  filter,  and  in  this  way  the  bodies  of  the  bacilli,  in  as  far 
as  they  were  not  of  ultra  microscopical  size,  were  removed, 
we  found  that  the  action  of  the  tuberculin  had  decreased  as 
far  as  quantity  was  concerned,  but  had  retained  the  same 
qualitative  properties.  From  this  it  is  evident  that  the  action 
of  tuberculin  is  connected  with  the  bodies  of  the  bacilli,  but 
that  probably  a  part  of  these  bodies  are  present  in  particles 
of  so  ultra-microscopical  a  size  that  they  pass  through  the 
candles  of  the  filter.  Already  Jadassohn  has  expressed  a 
similar  suggestion  in  criticizing  the  theory  of  the  tubercle 
bacilli  toxin  of  Klingmiiller. 

The  action  of  tuberculin,  tlierefore,  is  due  to  the  bodies 
of  the  bacilli  it  contains,  whether  they  are  present  whole, 
or,  on  the  other  hand,  are  crushed  to  such  an  extent  that  they 
pass  the  pores  of  the  filter. 

In  order  to  understand  the  action  of  tuberculin  it  is  more 
simple  to  apply  the  fundamental  doctrines  of  bacteriolysis 
which  have  practically  been  proved,  than  that  one  should 
have  to  seek  for  an  explanation  in  the  action  of  albuniino- 
lysine ;  this  would,  however,  not  lead  to  very  important 
differences,  since,  according  to  our  explanations,  it  is  highly 
probable  that  an  analogy  exists  between  bacteriolysis  and 
albuminolysis. 

The  particles  of  tuberculin  in  themselves  do  not  become 
active  in  the  animal  body,  especially  because  we  must  assume 
that  to  judge  by  its  chemical  structure  the  tubercle  bacillus 
is  not  easily  absorbed,  and  probably  may  resist  bacteriolysis 
to  a  very  great  extent.  It  is  only  the  lysine,  in  this  case 
the  bacteriolysine,  which  brings  into  activity  the  substances 


122  THE  OPHTHALMIC  AND  CUTANEOUS 

contained  in  the  particles  of  the  tubercle  bacilli,  in  accord- 
ance with  the  ancient  medical  phrase  corpora  noyi  agiint  nisi 
soluta. 

It  is  in  accordance  with  this  postulate  that  a  body  which 
has  never  before  come  in  contact  with  the  products  of  tubercle 
bacilli  does  not  react  on  tuberculin  as  long  as  the  doses 
applied  are  not  inany  times  the  size  of  those  which  are 
effective  in  the  case  of  tuberculous  bodies.  The  bacterio- 
lysine  substances  which  may  be  assumed  to  exist  m  the 
normal  body  are  not  sufficiently  abundant  to  create  an 
amount  great  enough  for  producing  effects.  Furthermore, 
when  tubercle  bacilli  substance  is  introduced  for  the  first 
time  there  is  no  hyper-sensibility  whatever,  which  seems  to 
be  necessary  before  a  reaction  can  occur. 

From  the  curve  figures  it  may  be  seen  to  what  extent  the 
substances,  which  bring  into  activity  the  toxins  contained 
in  the  fragments  of  the  bacteria,  are  present  in  each  particular 
case. 

As  mentioned  before,  it  is  probable  that  in  individuals  who 
have  never  before  come  in  contact  with  the  tubercle  bacilli, 
e.g.,  in  the  infant,  the  tubercle  bacilli  which  are  introduced  b)' 
means  of  the  tuberculin  remain  where  they  are.  At  any 
rate  it  does  not  produce  a  reaction,  so  that  in  such  cases  no 
reaction  bodies — the  bacteriolysine  substances,  the  existence 
of  which  we  have  assumed — are  present.  These  bacteriolysine 
substances  are  apparently  present  in  different  quantities  in 
different  stages  of  tuberculosis.  This  may  be  concluded  from 
the  fact  that  the  maximum  point  of  the  reaction  curve  is 
reached  in  each  case  after  a  different  period  of  time.  The 
differences  in  the  amount  of  bacteriolysine  present — in  as  far 
as  this  may  be  judged  from  the  course  of  the  curve — are 
not  very  great  in  the  case  of  actual  tuberculosis,  because  in 
all  tuberculous  individuals  the  reaction  commences  after  a 
fairly  equal  space  of  time,  and  only  shows  differences  in  the 
reaching  of  the  maximum  point.  The  difference  is,  bacterio- 
lysine between  non-infected  and  infected  individuals  corre- 
sponds in  all  essential  points  with  the  experiences  obtained  in 
other  ways  as  to  the  amount  of  bacteriolysine  in  infected  and 
non-infected  cases. 

We  will  here  say  a  few  words  as  to  whether  the  symptoms 
to  be  observed  clinically  in  tuberculosis  can  be  explained  by 
the  presence  of  bacteriolysine  substances  (for  as  such  we 
regard  the  much-discussed  anti-tubercular  substances).      We 


5. 
inn. 

John 

Rah 

,  Sons  K 

5:~  Dam 

Curve  Table 

■I'sso/i,  Ltd.,  I. on 

X. 

don. 

i      i           i            <      1 

\ 

1 
_       1 

'      1           1           1     1 

1      1      1      1      1 

showed   exacerbations  like   shoots,   analogous 
ranees  which  I,  for  instance,  had  found  in  se- 

rum disease. 

1      1      i      1           , 

, 

1 
1 

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losis 

01' 

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VI. 

l 

ni. 

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</// 

IX. 

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)a)'. 

Wolff-Eisner  and  Teichmann. 


Cutaneous  Reaction  in  clinically  healthy  individuals. 

Third  repetition  of  the  cutaneous  inoculation  in  Dr.  Teichmanr 


Curve  Table  X. 


1 

- 

~r 

"~ 

i   i   ! 

1 

I 

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n 

m 

Th    1    t                     b    •     d     '        I           h    r'         d 

- 

l. 

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t 

)  the  appearances  which  I,  for  instance,  had  found  in  se- 
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.■    t    e    «  70  B  It  7f  rs  so  a  St-mmiv. 

I.   D„y 

Hyper-sensibility  and  lasting  reaction  curvi 


//-  rioy  HI.  Day  IV.  Da} 

(Dr.  T.) 

Wolff- Eisner,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


V.        I'l      VIL      17//.      /.v.     -V.  Day. 


ds  of  Tuberculin. 


Curve  Table  XI. 


John  Bale,  Sons  <!V  Daiiielssou ,  Ltd.,  London. 


l_-_. 


\- 


IV.  Day. 

<— X— X-  Reddening  ■! 
"■  — Infiltration/ 

culosis. 


/'-.         VI.      VII.       VIII.       IX.      X.    Day. 
concentrated  Ruch-Enoch  tuberculin. 


Curve  Table  XL 


Course  of  the  Cutaneous  Reaction  by  the  use  of  different  kinds  of  Tuberculin. 

According  to  Wolff-Eisner  and  Teichmann.  Jekf,  BaU,  S<mi  &■  DaniihMu.  Ltd..  Uudcn. 


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?     12  rt     IG  fS     20   :^    29-Ifou/s. 

I.   Day  If.    Day 

■  Infiltration  I  *^^'''*'  filtered  Ruch-Enoch  tuberculin. 

Wolff-Eisne 


///.    Day. 
'  T-f:!.!"!!!!!  ?  tuberculol. 


I  nfi  Illation  f 
r,  The  Ophthalmic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


/:        77,       r//.       17//.       /X.      X.   Day. 
■  concentrated  Ruch-Enoch  tuberculin. 


DIAGNOSIS    OF    TUBERCULOSIS  123 

assume  that  under  the  action  ot  bacteriolysine  endotoxin  sub- 
stances are  hberated  from  the  tubercle  bacilli.  The  liberation 
of  such  substances  in  dififerent  masses  explains  the  increases 
in  temperature,  and  its  decreases,  as  also  the  night-sweating, 
&c.,  in  accordance  with  the  old  observation  that  small  amounts 
of  endotoxins  cause  an  increase  in  the  temperature  and 
leucocytosis,  whereas  large  amounts  produce  a  decrease  in 
the  temperature  and  negative   leucocytosis. 

Also  the  fact  that  fever  occurs  after  the  injection  of  tuber- 
culin in  tuberculous  individuals  is  explained  by  the  amount 
of  bacteriolysine  substance,  as  also  the  absence  of  fever  in  the 
non-tuberculous.  And  what  is  more  important  still,  also  the 
observation  made  by  Wassermann  to  the  effect  that  tuberculin 
and  anti-tuberculin  are  complementary  one  to  the  other 
becomes  quite  inteUigible  when,  instead  of  thinking  of  tuber- 
culin, we  think  of  fragments  of  tubercle  bacilli,  and  instead  of 
anti-tuberculin,  of  bacteriolysine.  It  is  a  very  well-known  fact 
that  bacteria  receptor  -|-  amboceptor  ----  immune  body  =  bac- 
teriolysine represent  the  complement  for  the  accomplishment 
of  the  lysis. 

Thus  we  find,  by  ohservlng  the  curves  in  all  individuals 
infected  with  tuberculosis,  that  a  substance  is  present  which  is 
capable  of  liberating  certain  substances  from  the  fragments  of 
tlie  tubercle  bacilli  in  tuberculin,  thus  producing  the  tuberculin 
reaction,  be  it  a  cutaneous,  a  conjunctival,  or  a  general  reaction. 
In  this  manner  our  investigations  show  that /or  all  tuberculous 
cases  a  uniform  change  of  condition  occurs  from  the  normal. 

In  reference  to  this  uniformity  in  the  change  of  the 
conditions  in  all  cases  of  tuberculosis  (allergy),  our  investiga- 
tions, however,  also  show  that  great  differences  exist  in  the 
reactive  capacity  of  the  respective  forms  of  tuberculosis,  and 
thus  it  is  found  that  the  reaction  is  a  highly  complex  pheno- 
menon which  is  composed  of  the  lysis,  the  fragments  of  the 
bacilli,  and  the  action  on  the  body  of  the  liberated  toxins, 
which  differs  according  to  the  degree  of  hyper-sensibility. 

To  synthesize  it  in  other  words :  The  non-infected  in- 
dividual does  not  react  at  all,  because  lysine  substances  in 
him  are  absent,  which  otherwise  would  rapidly  succeed  in 
liberating  toxins  from  the  fragments  of  bacilli  in  themselves 
unabsorptive. 

The  tubercle,  as  is  without  a  doubt  indicated  by  the  curves, 
liberates  active  substances  from  the  bacilli  fragments.  The 
reaction  on  these  substances  by  the  tuberculous,  however,  is, 


124  THE  OPHTHALMIC  AND  CUTANEOUS 

as  seen  in  the  curves,  very  different,  and  depends  on  the 
reactive  capacity  of  the  body  at  the  time,  governed  by  uniform 
law^s  which  themselves  are  indicated  by  the  curves. 

The  reactive  capacity  of  the  body  is  governed  by  the 
already  familiar  laws  of  hyper-sensibility  ;  that  is  to  say,  if, 
for  the  moment,  we  leave  out  of  account  the  absence  of 
the  reaction  in  moribund  cases.  Clinically,  hyper-sensibility 
expresses  itself  in  two  ways  :  (1)  as  an  extremely  rapid  re- 
action, frequently  of  relatively  little  intensity  ;  and  (2)  as  a 
rapid  and  excessively  strong  reaction. 

Both  forms  of  hyper-sensibility  are  already  familiar  by 
reason  of  occurring  in  the  serum  disease,^  and  the  experience 
gathered  in  the  case  of  tuberculin  and  in  serum  disease 
shows  that  these  two  forms  of  reaction  are  connected  very 
closely  with  hyper-sensibility,  and  have  no  direct  connection 
with  the  nature  of  the  substance  introduced  as  capable  of 
life  and  of  propagation. 

Both  forms  of  hyper-sensibility  occur  in  the  tuberculin 
reaction  and  can,  without  straining  the  matter,  be  read  from 
the  curves  represented  in  this  book.  The  rapid  and  strong 
reaction  corresponds  with  our  specific  normal  type ;  the  reac- 
tion which  sets  on  rapidly  and  takes  a  rapid  course  with  little 
intensity  corresponds  to  the  rapid  form  of  hyper-sensibility 
mentioned.  A  different  significance  is  to  be  attached  to  either 
form  of  tuberculin  reaction.  The  rapidly  passing  reactions  of 
little  intensity  are  of  unfavourable  augury,  whereas  the  more 
intense  and  less  rapid  reaction  is,  prognostically  speaking,  the 
more  favourable  one,  and  finally  gives  localized  results,  which 
is  in  accordance  with  my  remarks  in  the  Verein  filr  innere 
Medizin  on  December  16,  1907. 

We  now  have  still  to  deal  with  the  thn-d  form,  the  late 
and  lasting  reaction,  from  the  standpoint  of  our  latest  views 
on  bacteriolysine.  As  mentioned  above,  it  occurs  in  those 
individuals  who  have  a  latent  tubercular  centre  :  that  is  to 
say,  in  most  cases  in  which  a  tuberculous  infection  has  come 
to  a  standstill  or  has  healed  up.  "Since  this  may  have  taken 
place  a  long  time  ago,  we  may  regard  it  as  probable  that  no 
great  amount  of  bacteriolysine  is  left.  This  view  corresponds 
with  the  slow  rise  of   the  reaction   to   its   maximum,    whilst 


'  We  will  not  deal  with  the  phenomena  of  hyper-sensibility  in  cases  of 
revaccination,  since  here  a  further  complication  is  present  in  the  shape 
of  a  living  causative  agent,  which,  of  course,  is  able  to  propagate. 


DIAGNOSIS   OF   TUBERCULOSIS  125 

these  individuals  at  the  same  time  show  a  ^reat  sensibihty 
witli  regard  to  the  gradually  liberated  substances  of  the 
tubercle  bacilli,  so  that  the  reaction  papule  remains  for  a 
week  or  longer.  Our  previous  explanations  have  shown 
that  we  regard  the  hyper-sensibility,  as  such,  as  a  teleological 
phenomenon — especially  with  regard  to  tuberculin — which 
hinders  the  progress  of  the  tubercle  bacillus.  One  might 
enquire  why,  if  we  accept  the  presence  of  bacteriolysine  sub- 
stances, they  do  not  put  an  end  to  the  battle  against  the 
tubercle  bacillus  by  means  of  bacteriolysis,  and  in  that  case 
why  should  there  be  hyper-sensibility  ?  Considering  the  com- 
plex nature  of  all  phenomena  of  immunity,  such  a  question 
would  be  rather  an  unnecessary  one,  and  a  little  while  ago 
we  explained  that  also  in  the  case  of  infections  in  which  the 
bacteriolytic  form  of  immunity  may  be  regarded  as  proven, 
as,  for  instance,  in  the  case  of  typhoid  and  cholera,  hyper- 
sensibility  plays  a  very  important  role  with  regard  to  the 
infection.  On  the  other  hand,  however,  it  cannot  be  denied 
that  the  protection  depending  on  hyper-sensibility  is  like  a 
two-edged  sword,  and,  like  every  protective  action  depending 
on  hyper-sensibility,  may  become  a  danger  to  the  body  itself 
{Berl  klin.   Wochenschr.,  1907,  No.  38). 

Now  in  the  case  of  the  tubercle  bacillus  special  condi- 
tions prevail,  putting  the  importance  of  the  hyper-sensibility 
reaction  in  the  right  light.  The  tubercle  bacillus  itself,  as 
we  have  shown  above,  offers  great  resistance  to  bacteriolysis. 
The  tubercle,  as  we  know,  is  non-vascular,  and  it  is  very 
difficult  for  the  bacteriolysine  substances  contained  in  the 
blood  serum  to  arrive  at  the  centre  of  the  tubercle.  By 
caseation  the  action  of  the  bacteriolysine  substances  is  still 
further  prevented,  since  only  those  parts  of  the  bacilli  can  be 
bacteriolyzed  which  enter  the  circulation'  by  means  of  absorp- 
tion, whilst  the  tubercle  bacilli  occupying  the  centre  of  the 
caseation  remain  quite  inaccessible  to  the  solution,  and  are 
always  capable  of  producing  new  bacteria  from  which,  when 
they  arrive  at  the  border  of  the  tubercle,  poisons  are  liberated 
by  means  of  absorption,  causing  the  so-called  hectic  clinical 
phase  of  the  disease. 

Since  the  one  form  of  hyper-sensibility  reaction,  the 
intense  reaction,  ma}'',  by  producing  a  wall  of  connective  tissue, 


'  The  fact  that   bacilli  enter   the  circulation  has  recently  been  proved 
by  Maniiorek  in  guinea-pigs. 


126  THE    OPHTHALMIC    vVND    CUTANEOUS 

encapsule  and  localize  the  infection,  and  in  this  way  heal  it, 
our  clinical  conclusions  have  been  justified  also  from  a  theo- 
retical point  of  view  concerning  the  prognostic  significance 
of  this  hyper-sensibility  reaction. 

Let  us  hope  that  the  path,  along  which  the  action  of  the 
tubercle  bacilli  is  regarded  from  a  new  standpoint,  may  lead 
us  to  further  scientific  and  practical  results. 

FURTHER  PARTICULARS  CONCERNING  THE  MECHANISM  OF 
TUBERCULIN  IMMUNITY  AND  OF  IMMUNITY  TO  TUBERCLE 
BACILLI. 

In  the  preceding  chapter  a  number  of  points  have  to  some 
extent  been  presented  antithetically  for  conciseness'  sake. 
There  are  but  few  problems,  however,  which  have  interested 
the  best  investigators  to  the  same  extent  as  that  concerning 
the  immunity  to  tuberculosis,  which,  as  a  rule,  is  looked  upon 
as  a  question  concerning  immunity  to  tuberculin.  Thus 
we  may  understand  why  it  is  necessary  for  us  to  say  a  few 
words  on  this  subject  in  view  of  the  extensive  literature  on 
the  subject. 

First  of  all,  authorities  are  not  as  yet  agreed  as  to  what 
tuberculin  really  is.  Marmorek  (Soc.  de  Biol.,  1907,  No.  H) 
regards  tuberculin  as  a  substance  which,  introduced  into  the 
body,  causes  the  tubercle  bacilli  to  secrete  the  true  toxin 
of  tuberculosis.  According  to  Alexander  {Berl.  klin.  Woclien- 
schr.,  1907,  Nos.  11-13),  tuberculin  does  not  constitute  an  anti- 
toxin to  tubercle  bacilli,  but  only  a  remedy  for  the  changes 
produced  by  the  tubercle  bacilli.  He  refers  to  the  explana- 
tions of  Wassermann,  who  says  that  "  tuberculin  only  fills  up 
the  holes  gnawed  into  the  wood  by  the  wood-worm  by  cica- 
tricial tissues." 

Our  own  conception  of  the  nature  of  tuberculin  may  be 
clearly  seen  from  the  explanations  in  the  preceding  chapter. 
Tuberculin  is  the  poison  incorporated  in  the  substance  of  the 
tubercle  bacillus,  which  it  contains  in  fragments.  It  is  an 
endotoxin,  and,  by  special  conditions  inherent  m  tlie  tubercle 
bacillus,  it  is  a  preservable  endotoxin. 

I  must  now  give  the  historical  progress  of  my  investigations. 
Since  different  tuberculin  preparations  exist  with  apparently 
different  efficacy,  I  was  not  able  in  the  beginning  to  identify 
the  action  of  tuberculin  with  that  of  the  tubercle  bacilli  (not 
even  in  a  qualitative  sense,  and  now  I  only  recognize  a 
quantitative  difference    in    the  action).      Therefore  I    at  first 


DIAGNOSIS   OF    TUBERCULOSIS  127 

regarded  tuberculin  as  a  part  of  the  poison  of  the  tubercle 
bacilli  ;  I  did  not  start  with  the  preconceived  notion  that 
in  tuberculin  we  have  to  do  with  endotoxin  substances.  As 
a  matter  of  fact,  I  was  rather  inclined  to  regard  tuberculin 
as  a  toxin,  on  the  generally  accepted  principle.  On  the  basis 
of  investigations  extending  over  a  good  many  years  concerning 
tuberculin  immunity  in  guinea-pigs,  I  had  even  come  to  the 
conclusion  that  most  likely  no  endotoxin  was  present  in  the 
case  of  tuberculin,  as  the  hyper-sensibility  I  expected  with  an 
endotoxin  would  have  been  less  inconstant  and  more  decided. 
It  was  only  my  present  experiments  in  human  beings  which 
proved  to  me  that,  for  studying  tuberculin  immunity,  guinea- 
pigs  constitute  a  most  inappropriate  material. 

Even  if  we  succeed  in  killing  guinea-pigs  by  means  of  single 
or  repeated  injections  with  tuberculin,  no  typical  tuberculous 
changes  are  obtamed.  Only  in  very  rare  cases  have  I  found, 
after  repeated  injections  of  tuberculin,  small  lymphomata  in 
the  liver  ;  as  a  rule,  one  only  finds  a  considerable  hyperaemia 
in  all  organs,  which  is  not  specific,  and  which  I  regard  as 
characteristic  for  the  so-called  albumin-death  in  which  it  is 
always  found.  It  is  of  interest  to  find  that  Lagriffoul  {Soc. 
de  Biol.,  1907,  No.  1),  after  having  killed  guinea-pigs  by  means 
of  large  masses  of  homogeneous  culture  of  tubercle  bacilli, 
also  observed  the  absence  of  all  tubercles,  but  found  hyper- 
semia  in  all  the  organs. 

From  these  experiments,  which  I  have  never  published, 
no  other  conclusion  can  be  drawn  than  that  the  guinea-pig 
is  not  appropriate  material  for  the  study  of  the  mechanism 
of  tuberculin  immunity. 

But  now  the  observation  has  been  made  by  Stadelmann, 
Teichmann  and  myself,  that  a  local  reaction  was  not  shown, 
not  only  in  extreme  phthisical  cases,  in  which  the  incapacitij 
to  react,  supposed  to  exist  by  other  authors,  might  find  an 
acceptable  explanation,  but  also  in  a  fairly  large  number  of 
people,  most  of  whom  (though  not  by  any  means  all),  it  is  true, 
showed  changes  of  a  fairly  advanced  character.  This  we  con- 
nected with  a  fact,  which  at  any  time  can  easily  be  verified, 
namely,  that  very  frequently  these  individuals  do  not  react  to 
the  subcutaneous  injection  of  tuberculin. 

The  simplest  explanation  of  this  phenomenon  would  be  to 
assume  that  the  negative  reaction  is  caused  by  the  fact  that 
the  tissues  of  these  individuals  are  continuously  in  contact 
with  tuberculin,  so  that  their  bodies  are  saturated  with  it. 


128  THE  OPHTHALMIC  AND  CUTANEOUS 

This  hypothesis  has  apparently  been  confirmed  by  the 
experiments  of  Calmette,  Breton,  and  Petit  in  rabbits,  show- 
ing that  there  is  a  positive  conjunctival  reaction,  if  sixteen 
hours  before  its  application  small  amounts  of  tuberculin 
(1  to  5  milligrammes)  have  been  injected,  and  a  negative  one 
when  large  amounts  (10  to  100  milligrammes)  have  been  in- 
troduced. 

Thus  it  had  to  be  determined  whether  tuberculin  was 
circulating  in  the  serum  of  tuberculous  patients  who  had 
not  given  either  a  positive  cutaneous  or  a  conjunctival  reac- 
tion. The  technique  of  such  experiments  is  very  simple. 
It  suffices  to  obtain  two  or  three  drops  of  blood  from  a 
capillary,  as  in  the  case  of  determining  the  haemoglobin. 
In  four  cases  7w  tuberculin  could  be  found  in  the  serum  of 
individuals  without  reaction,  neither  by  application  of  the 
cutaneous  nor  by  that  of  conjunctival  reaction.  To  deter- 
mine the  presence  of  tuberculin  by  means  of  the  local  reactions 
we  had  to  make  use  of  a  test  individual  in  whom  the  sensitive- 
ness to  tuberculin  had  been  quantitatively  diminished,  and  who 
still  gave  a  distinct  reaction  to  a  1  in  1,000  solution  of  tuber- 
culin.^ Nor  has  Calmette  found  tuberculin  circulating  in  the 
serum  of  tuberculous  patients.^ 

The  apparently  well-founded  theory,  that  the  incapacity  of 
the  tuberculous  individual  to  react  to  tuberculin  is  due  to  the 
continuous  contact  of  his  body  with  tuberculin,  could  not  be 
maintained  after  the  results  of  the  experiments,  which  showed 
that  but  very  little  tuberculin  circulates  in  the  serum. 

Since,  however,  we  do  assume  that  tuberculin  is  formed  in 
the  body  of  a  tuberculous  person,  but  is  not  to  be  found  in  the 
serum,  we  must  conclude  that  it  disappears  somewhere  in  the 
body.  And  in  fact,  a  simple  experiment  showed  that  the 
tuberculin  injected  into  a  normal  guinea-pig,  which  had  in  no 
way  been  treated  in  advance,  disappears  almost  altogether  in 
twenty-four  hours  time. 

•  Serum  of  three  phthisical  individuals  (third  stage),  Ebelt,  Grossmann, 
Albrecht  (October  23,  1907).  Test  individual,  Kleindienst,  the  course  of 
whose  reaction  is  indicated  by  one  of  the  curve  tables  added. 

^Also  Arloing  (Soc.  de  Biol.,  1907,  No.  23).  He,  however,  worked 
with  two  unknown  factors,  since  to  determine  the  amount  of  tuberculin 
present  in  the  serum,  he  experimented  with  a  guinea-pig,  of  which  animal 
the  reactive  capacity,  and  more  especially  the  quantitative  sensitiveness  to 
tuberculin,  has  not,  as  yet,  been  definitely  ascertained.  So  far  man  only 
can  be  regarded  as  suitable  for  such  experiments. 


DIAGNOSIS   OF   TUBERCULOSIS  129 

The  Experiment. — A  guinea-pig  of  -200  grammes  weight 
was  injected  with  a  1  c.cm.  of  old  tuberculin  of  Koch,  and 
was  killed  twenty-four  hours  after  by  being  bled  to  death. 
A  scraping  of  an  organ  was  produced  by  means  of  a  Latapio 
apparatus  as  modified  by  Leitz.  Now,  if  it  is  assumed  that 
the  tuberculin  is  dispersed  houjogeneously  through  the  guinea- 
pig,  one  must  also  assume  the  presence  in  the  guinea-pig  of 
|-  per  cent,  concentration  of  tuberculin. 

Again,  if  tuberculin  were  distributed  unequally  over  the 
different  organs,  a  supposition  which  may  be  regarded  as 
possible,  some  organs  would  give  a  strong  and  others  a  weak 
local  tuberculin  reaction. 

But  neither  in  the  serum  nor  in  the  organs  of  the  guinea- 
pig  was  an  amount  of  active  tuberculin  present  sufficient  to 
produce  a  cutaneous  or  conjunctival  reaction  in  appropriate 
test  individuals.  Thus  it  is  demonstrated  that  the  tuberculin 
disappears  after  a  very  short  tune  even  in  the  non-prepared 
animal.  But  what  mechanism  causes  this  disappearance  ? 
The  following  possibilities  exist :  If  tuberculin  is  a  dissolved 
toxin,  its  disappearance  may  be  due  to  antitoxin  substances, 
by  lysis  and  attraction  in  a  manner  similar  to  that  which  I 
have  shown  to  occur  in  the  case  of  tetanus  toxin  and  other 
poisons  ;  or  we  may  have  lo  do  with  bodily  elements,  and 
in  this  case  its  disappearance  w^ould  be  due  to  decomposition 
and  neutralization,  or  to  being  taken  up  in  cells  (phago- 
cytosis). 

For  instance,  the  escape  through  the  kidneys,  we  thought, 
would  be  improbable,  and  from  the  beginning  we  excluded 
this  possibility:  those  who  disagree  with  our  view  can  easily 
prove  the  fact  for  themselves. 

It  has  always  been  very  difficult  to  decide  these  questions, 
because  tuberculin  constituted  a  toxin  which  could  not  be 
titrated,  and  its  action  could  only  be  tested  in  tuberculous 
individuals.  The  subcutaneous  tuberculin  injection  excluded 
repetition  of  the  experiment,  and  also  experimentation  in 
man.  The  local  reaction,  which  may  be  applied  a  second 
time,  proves  to  be  a  very  valuable  aid  in  investigating  im- 
munity. 

The  presence  of  an  antitoxin  in  the  serum  of  a  non- 
prepared  guinea-pig  (which,  as  we  know,  may  be  regarded 
as  without  protection  with  regard  to  tubercular  infection) 
was  not  very  probable.  Experiments  enumerated  by  Petit 
showed  that  in  the  serum  of  tuberculous  rabbits  no  antitoxin 
9 


130  THE  OPHTHALMIC  AND  CUTANEOUS 

is  found,  that  is  to  say,  no^substances  which  could  neutralize 
tuberculin,  nor  could  they  be  found  in  the  serum  of  rabbits 
immunized  with  tuberculin.  My  own  experiments  had  exactly 
the  same  results. 

Our  tests  also  showed  that  the  guinea-pig  can  stand 
enormous  amounts  of  tuberculin.^ 

A  few  guinea-pigs  have  been  injected  with  10  c.cm.  and 
even  more  of  undiluted  tuberculin  (Koch's  old  tuberculin, 
and  other  preparations)  within  a  very  short  time.  If  very 
large  amounts  are  injected  a  small  or  minimal  reaction  is 
brought  about,  which  is  limited  to  vacillations  in  the 
temperature. 

Thus,  in  the  case  of  the  guinea-pig  the  paradox  was  found 
that  if  this  animal — and  vian,  in  an  analogous  way — was  not 
sensitive  to  tuberculin,  it  proved  to  be  without  protection 
against  infection  by  means  of  tubercle  bacilli.  This  fact 
contradicts  all  our  other  experiences  concerning  the  nature 
of  toxin.  The  presence  of  antitoxin  in  other  cases  prevents 
the  harmful  action  of  the  tetanus  and  diphtheria  bacilli.  It 
would  seem  as  if  there  is  no  other  way  of  solving  these 
difticulties  than  by  assuming  that  imiminity  with  regard  to 
tuberculin  is  not  by  any  means  identical  with  immunity  in 
regard  to  tubercle  baciUi,  and  a  second  possibility  would  be 
that  it  is  just  this  incapacity  to  react  which  enables  the 
bacteria  to  make  progress,  just  in  the  same  way  as  has  been 
assumed  to  exist  in  the  case  of  the  lepra  bacillus  by  Pfeiffer ; 
the  lepra  bacillus  is  almost  poisonless,  the  body  is  not  stimu- 
lated to  produce  a  reaction,  and  b}^  reason  of  this  absence  of 
a  reaction  the  bacillus  gradually  invades  the  whole  body. 
A  short  time  ago^  I  pointed  to  the  part  played  by  hyper- 
sensibility  in  combating  infections,  and  now  such  an  explana- 
tion   seemed    to   open    up    the    possibility   of   explaining   the 


'  According  to  Walilen  {Soc.  de  Biol.,  1904,  No.  8),  it  does  not  as  a 
rule  succumb  to  20  c.cm.  of  the  culture  filtrate  ;  the  injection  only  causes 
a  swiftly  passing  rise  in  the  temperature.  Repeated  injections  of  0"01  at 
intervals  of  eight  days  cause  rises  in  the  temperature  which  soon  pass, 
no  decrease  in  weight,  and  cachexia. 

Hantjens  {(r?/(7sc7/r.  voor  Geneesh.,  So.  7)  by  dialyzing  tubercle  bacilli 
in  water,  believes  he  has  obtained  substances  which  differ  from  Kocli's 
tuberculin,  and  which  coiTespond  with  the  "  toxins '"  secreted  in  the  living 
individual. 

-  Bcrl.  klin.  WoeheiiscJn:,  1907. 


DIAGNOSIS    OF   TUBERCULOSIS  181 

observation,  however  paradoxical  it  may  seem  at  first  sight, 
that  insensibilifij  to  toxins  signifies  harm,  whilst  sensihilitij, 
even  hyper-sensibility,  is  of  advantage  to  the  body. 

Practitioners  who  observe  accurately  have  always  very 
clearly  found  this  difference  between  immunity  to  tuberculin 
and  immunity  to  tubercle  bacilli.  Compare,  for  instance,  the 
publications  of  Kohler  on  the  subject,  who  in  the  Transactions 
of  the  Fourth  Congress  for  Tuberculosis  in  Berlin,  Brauers 
Beitrage,  vol.  viii.,  p.  75,  says,  "  that  notwithstanding  the 
absolute  insensibility  to  tuberculin,  the  tuberculous  process  in 
the  interior  of  the  organism  may  continue  and  may  even 
spread." 

After  this  we  get  the  explanation  of  Wassermann  which 
claims  to  solve  this  paradox.  We  have  already  quoted  it  in 
former  chapters  of  this  work.  "  Tuberculin  encounters  anti- 
tuberculin  in  the  tubercular  centre  and  thus  the  reaction  is 
produced.  The  absence  of  the  reaction  may  be  explained  by 
the  fact  that  the  anti-tuberculin  circulates  in  the  serum,  and 
by  holding  up  the  tuberculin  it  prevents  the  latter  from  enter- 
ing the  seat  of  the  disease. 

I  could  not  agree  with  this  view,  which  Pirquet  put  for- 
ward in  an  analogous  way  when  explaining  the  causation  of 
the  serum  disease,-  because  already  in  Pirquet's  case  I  had 
objected  to  the  principle  that  the  encounter  betw'een  a  sub- 
stance and  its  anti-substance  could  produce  a  reaction.  We 
must  mention  that  Pirquet  ("  Vers.  D.  Naturf.  u.  Aerzte," 
Dresden,  1907)  has  also  applied  this  much  criticized  view  of 
the  cutaneous  tuberculin  reaction,  although  his  opinions  con- 
cerning the  causation  of  the  serum  disease  have,  at  all  events 
to  some  extent,  been  modified  after  my  explanations*  and  have 
approached  my  views  (see  his  opinions  on  re-vaccination).^ 

The  genesis  of  the  Wassermann  theory  is  of  very  great 
interest.  Wassermann  originally  regarded  the  tuberculin 
anti-substances  as  lysins  (that  is  to  say,  bacteriolysins). 

The  tubercle  bacillus,  like  other  bacilli,  produces  agglu- 
tinin (Arloing  and  Courmont,  Acad,  des  Sciences,  Paris,  May 
16  and  September  19,  1898),  precipitin  (Marzagalli,  Ann.  1st. 
Maragliano,  1904,  f.  1.),  and  Bonome,  Zentralb.  f.  Bakt.,  vol. 


'  "  Die  Serumkranklieit,''  Wien,  Deuticke,  1907. 

-  "  Die  Eiweissiiuinunitiit  und  ihre  Beziehungen  zur  SeruuiArankheit," 
Zentralb.  f.  Bakt.,  vol.  40,  No.  3. 

^  "  Die  Yacoinution."     ^Vien,  Deuticke,  1907. 


132  THE  OPHTHALMIC  AND  CUTANEOUS 

48,  p.  891).  The  probable  presence  of  bacteriolysins  has 
been  shown  by  MarzagalH  and  Figari  (Ann.  1st.  Maragliano, 
1904,  part  I).  The  experiments  of  Bordet  and  Gengou  (Acad, 
des  Sciences,  Paris,  August  3,  1903),  of  Wassermann  and  Bruck 
(Deiitsch.  med.  Wochenschr.,  1906),  and  Citron  {Berlin,  klin. 
Wochenschr,  1907,  No.  36)  pointed  to  the  presence  of  ambo- 
ceptors, though  not  in  all  cases.  They  were  especially  found 
in  animals  treated  with  tuberculin,  which  did  not  any  longer 
react  on  tuberculin  injections.  Thus  gradually  the  amboceptor 
became  an  anti-tuberculin,  almost  an  antitoxin.  And  again 
such  important  voices  as  those  of  Morgenroth  and  Rabmo- 
witsch  (Deutsch.  med.  Wochenschr.,  1907,  No.  18)  expressed 
themselves  against  the  conception  of  the  amboceptors  as 
bacteriolysin  in  the  following  words  :  "  We  must  especially 
emphasize  the  fact  that  up  to  the  present  it  has  not  been 
possible  to  identify  the  substances  active  in  this  process  with 
any  of  the  known  immune  substances.  In  the  same  manner 
it  is  not  possible  to  identify  the  antithesis  of  the  tuberculin." 
Wassermann,  in  the  course  of  his  work,  gradually  tends  more 
and  more  to  use  the  terms  "  anti-substances"  and  "  anti-tuber- 
culin "  in  the  sense  of  antitoxin  ;  this  may  to  some  extent 
have  been  caused  by  the  enthusiastic  references  on  the  part 
of  practitioners  who  always  spoke  of  antitoxin.  Eecently 
I  have  given  a  general  warning  against  using  the  expression 
"  anti-substances  "  for  "reaction  substances,"  since  in  doing  so 
one  may  easily  disseminate  mistaken  conceptions  concerning 
the  nature  of  precipitin,  bacteriolysin,  agglutinin,  &c.  [Berl. 
hlin.  Wochenschr.,  1907).  How  well  justified  is  this  warning, 
which  at  first  sight  only  seems  to  touch  the  nomenclature,  may 
be  seen  from  the  fact  that  a  man  like  Wassermann,  who  so 
thoroughly  understands  the  whole  of  the  science  of  immunity, 
has  actually  yielded  to  the  suggestive  powder  of  this  designation. 
The  construction  of  Wassermann's  theory  concerning  the 
blockading  of  the  tubercular  centre,  preventing  the  tuberculin 
from  entering,  is  only  possible  on  the  basis  of  antitoxin,  and 
not  any  longer  on  that  of  bacteriolysin. 

The  presence  of  bacteriolytic  substances  is  not  only 
indicated  by  our  curves,  which  clearly  show  the  liberation  of 
active  substances  under  the  influence  of  such  substances 
as  are  at  present  onl}^  in  the  bodies  of  tuberculous  indi- 
viduals, but  is  also  demonstrated  by  the  observations  of 
Marmoreck   and   Bail.     Finally,    the   fever   reactions    in    the 


DIAGNOSIS   OF   TUBERCULOSIS  133 

tuberculous  are  to  be  connected  with  the  liberation  of  the 
tubercle  bacilli  toxiiis.'- 

The  theory  of  Wasserniann,  as  originally  set  forth,  assumed 
lysin  substances  as  anti-tuberculin,  the  existence  of  which 
was  demonstrated  by  the  process  of  avoiding  the  encounter 
of  the  complementary  substance.  The  voluminous  publication 
of  Citron^  shows  that  these  anti-tuberculin  substances  are  not 
present  in  all  cases  of  tuberculosis,  but  only  in  a  number  of 
cases,  especially  in  those  individuals  who  had  been  treated 
with  tuberculin  during  some  time,  and  more  pronounced  in 
those  who  do  not  any  longer  give  a  reaction  when  fairly 
large  doses  of  tuberculin  are  administered. 

Our  own  investigations,  however,  show  that  these  sub- 
stances are  present  not  in  isolated  cases,  but  in  all  cases  of 
tuberculosis,  and  thus  they  show  that  there  is  a  tiniform 
change  in  the  condition  of  all  tuberculous  individuals. 

This  discovery  is  probable   also  from  a  clinical   point  of 

•  "  Ueber  Tubei'kuloseantikorper  unci  das  Wesen  der  Tuberkulinreaktion," 
Bert.  Idin  Wochenschr.,  1907,  No.  36. 

■'  Arloing  and  Deutsch  have  shown  that  tuberculous  guinea-pigs  react 
stronglj^  in  the  case  of  super-infection,  that  is  to  say  in  the  case  of  a 
renewed  introduction  of  tubercle  bacilli ;  if  introduced  through  the  peri- 
toneum the  reaction  is  stronger  still,  and  often  a  lymphocyte  exudation 
is  to  be  found  after  one  hour.  The  same  phenomenon  of  hyper-sensibility 
may  be  obtained  with  dead  bacilli.  The  exudation,  if  infected  together 
with  tubercle  bacilli,  may  cause  death  sometimes  in  less  than  twenty-four 
hours.  This  is  not  due  to  the  exudation  or  to  the  tubercle  bacilli  alone, 
not  even  when  large  doses  are  applied. 

Bail  {Wien.  klin.  Wochenschr.,  1904,  No.  30)  believes  that  in  such 
experiments  we  have  to  do  with  the  action  of  his  aggressin.  It  would 
seem  to  me,  however,  that  in  this  case  we  have  perfect  analogies  with  the 
action  of  tuberculin  in  infected  guinea-pigs.  The  bacteriolysin,  the 
presence  of  which  we  have  demonstrated  in  the  organism  of  the  tuberculous 
bodies  and  which  is  also  found  in  the  exudation,  liberates  the  toxin  sub- 
stances from  bacilli  (living)  and  fragments  of  bacilli  (tuberculin),  producing 
a  reaction  which  may  lead  to  death.  The  symptoms  are  of  too  acute  a 
character  to  leave  room  for  conceiving  the  presence  of  aggressin,  con- 
sidering the  slow  growth  of  the  tubercle  bacilli,  and  especially  when  we 
take  into  account  that  the  same  phenomena  may  be  produced  by  means 
of  dead  bacteria. 

Also  the  method  of  injecting  animals  with  suspected  fluid  matter 
(exudations,  &c.),  and  of  diagnosing  tuberculosis  alter  only  six  days  on  the 
basis  of  a  rise  in  the  temjierature  which  also  occurs  after  subcutaneous 
injection  of  tuberculin,  is  based  on  the  pi-esence  of  bacteriolysins. 

If  the  suspected  liquid  substance  contained  tubercle  bacilli,  bacterio- 
lysins have  already  been  formed  in  the  course  of  this  time,  liberating  the 


134  THEf'oPHTHALMIC   AND    CUTANEOUS 

view,  since  it  would  show  that  not  only  those  individuals  who 
are  treated  with  tuberculin  form  reaction  substances,  but  all 
those  who  come  in  contact  with  tubercle  bacilli  and  their 
derivatives — and  this,  of  course,  includes  tuberculin.  The 
individual  cases  of  tuberculosis  do  not  differ  essentially  by 
the  presence  of  a  different  amount  of  bacteriolysin  substances 
— or  of  hyper-sensibility,  for  that  matter — but  by  the  different 
symptoms  of  hyper-sensibility  which  follow  the  uniform  and 
fairly  easily  recognizable  laws  developed  in  the  preceding 
chapter. 

The  fact  that  in  all  cases  of  tuberculosis  we  find  bacterioly- 
sin— the  anti-tuberculin  of  .Wassermann — may  be  explained 
by  the  fact  that  Wassermann's  technique  for  the  production  of 
the  complementary  substance  is  certainly  very  ingenious  and 
complicated,  but,  considering  the  very  difticult  conditions,  is 
yet  crude.  Only  comparatively  large  amounts  of  bacterioly- 
sins    can    be    detected    by  'means  [of   it,    whereas    our   curve 


poisons  from  the  tuberculin  injected  six  days  afterwards,  and  leading  to 
a  rise  in  the  temperature  of  over  1*2°  (compare  Marnjoreck,  Soc.  de  Biol. 
1904,  No.  1,  and  Larrier,  Soc.  de  Biol.,  1904,  No.  4). 

My  investigations  make  me  doubt  that  the  guinea-pig  is  an  animal 
appropriate  for  such  experiments,  and  I  am  incHned  to  believe  that 
rabbits  would  be  better  subjects  :  even  an  infected  guinea-pig  is  less 
sensitive  to  tuberculin  than  an  infecteil  human  being.  The  fact  that  in  the 
case  of  a  guinea-pig  a  few  days  after  infection  (even  after  three  days) 
allergy  may  be  present  is  shown  by  the  observations  of  F.  Klemperer 
(see  the  chapter  on  the  application  of  the  reaction  in  animals),  who  has 
observed  a  cutaneous  reaction  after  only  three  days  in  the  case  of  infected 
guinea-pigs.  Furthermore,  the  presence  of  bacteriolysins  (even  moi-e 
distinct  than  in  tuberculous  human  individuals)  in  infected  guinea-pigs 
is  proved  by  Wassermann's  process  of  avoiding  the  encounter  of  the 
complementary  substance  (see  Berl.  Min.  Wochenschr.,  1907,  No.  36)  ; 
in  the  case  of  the  guinea-pig,  however,  the  clinical  symptoms  of  hyper- 
sensibility  are  few,  considering  the  toxins  liberated  by  the  lysin. 

The  acceptance  of  bacteriolysin  is  to  some  extent  supported  by  a 
practically  clinical  proof .  Marmoreck  (-BerZ.  Min.  Wochenschr.,  1907,^0  21) 
has  shown  that  if  guinea-pigs  are  subcutaneously  infected,  tubercle  bacilli 
circulate  in  the  blood  from  the  thirty-fifth  day  (tubercle  bacilli  sepsis). 
These  single  bacilli,  of  course,  can  be  demonstrated  only  in  the  case  of 
experiments  on  animals. 

Guinea-pigs  inoculated  with  these  tubercle  bacilH  which  circulate  in  the 
blood  only  die  after  a  good  many  months  (six  and  more).  This  indicates 
a  weakening  of  the  bacilli  in  the  blood,  which  probably  has  to  be  traced 
back  to  bacteriolysis,  especially  if  one  takes  into  consideration  that  bacteria- 
destroying  forces  must  be  present,  since  the  number  of  the  bacteria 
circulating  in  the  blood  remains  small. 


DIAGNOSIS    OF   TUBERCULOSIS  1H5 

method  constitutes  a  valuable  supplement  and  amplification 
of  Wassermann's  methods,  at  the  same  time  being  a  truly 
biological  method. 

The  objections  raised  against  Wassermann's  theory  by 
Weil  and  Morgenroth^  are  easily  explained  by  our  theory  and 
our  observations. 

It  is  therefore  unnecessary  for  us  to  dwell  upon  the  fact 
that  Ltidke  (Beitr.  z.  Klin.  d.  Tub.,  1907,  vol.  7,  No.  1) 
discovered  a  formation  of  anti-substance,  though  a  small  and 
ephemeral  one,  whereas  Morgenroth  and  Rabinowitsch,  on 
the  other  hand,  stated  its  absence  in  four  cases  which  had 
been  treated  with  tuberculin  (three  fresh  tuberculin,  one  old 
tuberculin). 

We  fully  agree  with  the  explanation  of  Morgenroth  and 
Babinowitsch  to  the  effect  that  the  accumulation  of  comple- 
mentary substance  cannot  explain  the  shrinking  of  the  tissue, 
because  the  amboceptor  itself  guides  the  complementary 
action  to  the  spot  where  it  accumulates.  The  shrinking,  we 
presume,  is  due  to  the  action  of  the  toxins  liberated  by  the 
bacteriolysis.  Also  the  hyper-sensibility  plays  a  part  in  the 
process  of  shrinking.  This  conception  is  not  only  very 
plausible,  but  it  also  finds  a  direct  proof  in  the  fact  that  the 
cutaneous  method  of  introducing  tuberculin  into  the  locally 
hyper-sensitive  tissue  (m  lupus)  does  not  always  produce  a 
papule,  but  sometimes  also  a  shrinkage  of  the  tissue,  an 
ulcer,  &c. 

Morgenroth  complains  that  no  theory  has  yet  been  brought 
forward  to  explain  the  action  of  tuberculin  ;  also  hyper-sensi- 
bility plays  a  part,  but  which  part  is  not  known.  It  con- 
stitutes a  crux  in  every  immunity  theory. 

I  believe  that  the  work  of  Teichmann  and  myself  offers 
the  theory  of  the  action  of  tuberculin  sought  for,  which  is 
entirely  based  on  the  article  appearing  in  1904  in  the  Zentralb. 
f.  Bakt.,  \o\.  37,  on  the  "  Grundgesetze  der  Immunitat."  In 
this  theory  the  laws  governing  the  hjjjjer-sensibilit;/  form  the 
integral  part. 

It  is  absolutely  necessary  to  clearly  distinguish  between  the 


'  Deutsche  med.  Wochenschr.,  1907,  Xo.  LS.  Morgenroth  and  Rabino- 
witsch explain  their  negative  results  by  sources  of  error  in  the  techniquf. 
the  complexity  of  which  (technical  as  well  as  theoretical)  is  recognized  bv 
Wassermann  himself.  It  is  just  this  which  gives  so  great  a  value  to  the 
technique  proposed  tor  the  detection  of  bacteriolysins. 


136  THE  OPHTHALMIC  AND  CUTANEOUS 

bacteriolysis  always  i^resent  in  tuherculosis  and  the  changing 
phenomena  of  hyper-sensibility ,  and  this  may  not  in  future  be 
left  out  of  account  when  an  endeavour  is  made  to  explain  the 
action  of  tuberculin. 

This  distinction  throws  a  very  clear  light  on  the  results 
and  possible  success  of  the  tuberculin  therapy.  The  injection 
of  not  too  large  doses  of  tuberculin  stimulates  the  formation 
of  bacteriolysin  substances.  These,  however,  are  always 
present  spontaneously,  as  explained  above.  Yet  there  can  be 
no  doubt  that  sometimes  such  a  stimulus  to  the  formation  of 
bacteriolysin  may  have  a  favourable  effect.  But  it  is  only  of 
use  as  long  as  it  does  not  transform  the  favourable  form  of 
the  hyper-sensibilit}'  reaction  of  the  body  (the  specific  normal 
reaction)  into  the  unfavourable  form  of  the  hyper-sensibility 
reaction  (rapid  reaction),  or  even  into  an  altogether  negative 
reaction.  Imbued  with  the  idea  of  antitoxic  immunity  and 
not  disheartened  by  unfavourable  results,  it  has  always  been 
sought  to  obtain  a  high  degree  of  immunity  to  tuberculosis. 
Since  this  method  of  investigation  may  often  result  in  an 
unfavourable  form  of  reactive  capacity,  it  constitutes  a  very 
dangerous  way  of  treating  tuberculosis,  and  has  always  been 
avoided  as  much  as  possible  by  experienced  clinicians.  We 
can  only  warn  most  emphatically  against  renewed  experi- 
ments in  this  direction.  The  intermittent  etappe  treatment, 
according  to  Petruschky,  which  does  not  regard  the  purpose 
of  immunization  to  be  the  absence  of  the  reaction,  possesses, 
from  a  theoretical  point  of  view,  more  chances  of  bringing 
about  the  most  favourable  results  and  of  causing  less  harm 
than  any  other  method  of  tuberculin  treatment.  For  some 
purposes  it  is  of  advantage  to  employ  the  opsonin  method 
which,  in  the  second  German  edition  of  this  work,  will  be 
dealt  with  more  extensively.  In  this  English  edition  I  may 
omit  this  chapter.  I  will  only  mention  here  that  the  opsonic 
index  does  not  run  parallel  with  the  cutaneous  and  conjunc- 
tival method ;  the  former  supplements  the  latter  in  a  raost 
desirable  manner. 

OBSERVATIONS      CONCERNING      TUBERCULIN      THERAPY      AND 
THE    TREATMENT   OF   TUBERCULOSIS. 

Lowenstein  and  Rappaport  {Deutsche  med.  WoclienscJir.,  1904,  p.  835) 
were  the  first  to  recognize  that  hyper-sensibility  plays  a  part  in  tubercular 
infection. 

Furthermore  they  have  shown  that  hyper-sensibility  with  regard  to  old 


DIAGNOSIS    OF   TUBERCULOSIS  187 

tuberculin  at  the  same  time  indicates  hyper-sensibility  witli  regard  to  all 
other  tuberculin  preparations.  This  they  express  in  a  form  (the  hyper-sensi- 
bility with  regard  to  the  derivatives  of  living  tubercle  bacilli,  which  they 
regard  as  a  certain  indication  of  the  presence  of  a  specific  substance  in 
tuberculin)  which  clearly  indicates  its  character  as  the  forerunner  of  our 
more  expansive  doctrine  concerning  the  identity  of  the  effect  of  tuberculin 
preparations  with  that  produced  by  the  living  tubercle  bacilli. 

In  their  sanatorium  patients  they  found  that  in  the  course  of  tuber- 
culosis the  hyper-sensibility  increased  ;  our  own  investigations  show  that 
when  it  has  reached  a  certain  point  it  decreases  again.  The  diffei-ence 
may  be  explained  by  the  fact  that  really  advanced  cases  hardly  ever  come 
to  the  sanatoria.  The  actual  correspondence  in  the  discoveries  may  be 
concluded  from  the  fact  that  in  cases  of  manifest  (open)  tuberculosis  they 
found  20  per  cent.,  in  closed  tuberculosis  66'3  per  cent,  of  hyper-sensibility 
after  the  subcutaneous  tuberculin  injection. 

The  essential  differences  between  our  own  views  and  those  of  Lowen- 
stein  and  Rappaport  are  to  the  effect  that  the  latter  regard  hyper-sensibility 
as  a  dangerous  condition,  and  a  negative  reaction  as  a  condition  of  innuunity 
and  of  favourable  augurj'. 

Their  explanations  fully  agree  with  the  views  concerning  immunity 
prevalent  at  the  time,  which  in  1904  (Zentralb.  f.  Bald.,  vol.  37)  I  en- 
deavoured to  oppose,  of  course  without  direct  success.  But  Lowenstein 
and  Eappaport  may  have  become  doubtful  as  to  the  correctness  of  their 
explanation  from  their  own  material ;  a  patient  who  had  been  treated  with 
tuberculin  was  found  after  a  year  to  react  to  the  small  dose  of  O'l  mg.,  tlnis 
distinctly  showing  lujpev-sensihiUty,  although  clinically  his  condition  was 
certainly  to  be  regarded  as  favourable. 

We  have  to  add  a  few  special  observations  to  our  general 
explanations  concerning  the  theory  of  tuberculin  therapy. 
To  cure  tuberculosis  almost  all  thinkable  ways  have  been  tried. 
Barthel-Neumann  {Wien.  hlin.  Wochensckr.,  1907,  No.  43) 
<aves  us  a  very  instructive  compendium  of  the  methods  em- 
ployed, and  a  peculiar  interest  is  attached  to  criticizing  these 
various  methods  from  the  present  theoretical  standpoint. 

The  treatment  of  pulmonary  cases  with  the  serum  of 
animals  which  are  naturally  immune,  or  at  any  rate  very 
resistant,  to  tuberculosis  represents  a  therapy  of  a  peculiar 
order.  It  is  designated  by  the  name  hoemocyne  therapy  ;  Link, 
Hericourt,  and  Richet  employed  serum  of  dog>,  Bouchard 
serum  of  goats,  Auclair  serum  of  fowls,  and  Maffucci  and  De 
Vestea  serum  of  sheep.  However,  this  therapy  has  not 
been  heard  much  of  recently. 

Then  we  come  to  the  long  series  of  investigators  who 
endeavoured  to  cure  tuberculosis  by  means  of  tuberculin,  and 
who  alternately  employed  weak  and  strong  doses  of  tiiis  sub- 
stance. Amongst  these,  Pfuhl,  Kitasato,  Bujwid,  Spengler, 
Petruschky,  are  amongst  the  most  important.     Some  of  the 


138  THE  OPHTHALMIC  AND  CUTANEOUS 

writers  on  this  subject  regarded  this  treatment  as  conducive 
to  life,  whilst  others  have  viewed  it  in  an  opposite  light. 
The  latter  view  was  especially  held  by  Metschnikoff  and 
Roux  and  Buchner,  who  plainly  declare  that  weak  doses 
have  no  effect  whatever,  whilst  large  ones  kill  the  animals 
sooner  than  the  infection  alone. 

The  treatment  by  means  of  tuberculin  has  frequently  been 
modified.  Beraneck  employs  a  specific  tuberculin  prepared 
with  tubercle  bacilli  obtained  from  the  patients  themselves 
(comp.  Krausse,  Hanover,  Zeitschrift  filr  Tuherkulose,  vol.  2, 
No.  5).  Klebs  has  carried  out  most  elaborate  experiments 
for  the  purpose  of  preparing  perfectly  innocuous  tuberculin, 
and  Landmann  worked  with  a  kind  of  very  concentrated 
tuberculin  prepared  in  a  special  manner,  the  so-called 
ttiberculol. 

Then  we  come  to  the  numerous  experiments  carried  out 
for  combating  tuberculous  infection  by  means  of  antitoxic 
serum.  Various  ways  have  been  tried  for  obtaining  such  sera. 
Predisposed  and  other  animals  were  treated  partly  with  tuber- 
culin, partly  with  tubercle  bacilli.  Auclair  endeavoured  to 
find  antitoxin  in  the  blood  of  tuberculous  fowls,  Viquerat  in 
the  serum  of  mules  infected  with  tuberculosis.  The  latter 
maintain  that  they  obtained  favourable  results  by  their  treat- 
ment ;  Eutkowski,  on  the  other  hand,  obtained  unfavourable 
results.  Tizzoni  and  Cantani  immunized  guinea-pigs  with 
tuberculin,  also  fish  and  horses  by  means  of  the  new  Koch 
tuberculin  (T.-R.).  Maragliano's  favourable  result,  as  Maxu- 
tow  expresses  it,  proved  nothing  more  than  that  guinea-pigs 
that  had  been  mfected  with  tuhercuUn  could  be  cured  by 
means  of  his  curative  serum,  not,  however,  guinea-pigs  into 
which  living  tubercle  bacilli  had  been  introduced.  His 
experiments  {Ann.  1st.  MaragL,  1904),  at  all  events,  are  worth 
consideration. 

A  great  deal  of  interest  attaches  to  those  experiments 
carried  out  with  a  view  of  obtaining  active  immunity  to 
tubercle  bacilli  ;  they  seem  to  have  the  greatest  chance  of  a 
successful  issue.  Maffucci  and  Di  Vestea  first  injected  dead, 
and  then  living  tubercle  bacilli,  and  found  that  the  infected 
guinea-pigs  lived  twenty-four  days  longer  than  the  control 
animals  (seventy-four  and  fifty  days  respectively).  Babes  and 
Broca  combined  the  treatment  by  tuberculin  with  that  by 
tubercle  bacilli.  They  first  injected  tuberculin  prepared  from 
tubercle  bacilli  of  birds,  then  living"  tubercle  bacilli  of  birds, 


DIAGNOSIS   OF   TUBERCULOSIS  139 

then  human  tubercuhn,  and  finally  living  tubercle  bacilli  of 
men.  Lastly,  Rodet  and  Granier,  and  Redon  and  Chenot, 
employed  tubercular  organs  of  immunization,  Bertarelli  {Ze7i- 
tralb.  f.  Bald.,  vol.  55,  p.  1)  subsequently  supplying  them 
with  the  theoretical  basis,  apparently  proving  by  means  of  a 
technique  (precipitin  technique) — which  1  believe  to  lead  to 
false  conclusions — that  the  substances  of  the  tubercle  can 
produce  independent  substances  from  the  anti-substances  of 
the  tubercle  bacilli. 

The  fact  that  so  great  a  number  of  unsuccessful  results  have 
thus  far  been  obtained  in  the  specific  treatment  of  tuberculosis 
is  not  surprising,  in  view  of  the  theories  developed  by  us  in 
regard  to  the  bad  prospects  of  the  production  of  antitoxin,  and 
that  all  these  methods  only  produce  hacteriolysin,  or  at  any 
rate  stimulate  the  formation  of  hacteriolysin  suijstances. 
From  our  experiments  it  is  evident  that  this  is  not  conducive 
to  any  important  curative  results,  and  on  this  basis  we  dis- 
agree with  the  view  of  AVassermann  and  Citron,  to  the  effect 
that  hacteriolysin  substances  are  present  in  all  cases  and  in  all 
stages  of  tuberculosis,  but  that  these  substances  alone — for 
reasons  fully  expounded  in  their  proper  place — are  not  capable 
of  deciding  the  battle  against  the  tubercle  bacilli  in  our  favour. 

But  it  becomes  all  the  more  clear  why  there  are  so  many 
unsuccessful  therapeutic  results  obtained  and  injuries  l)rought 
about  by  the  tuberculin  treatment  of  tuberculosis.  Our 
experiments  show  very  clearly  that  injury  is  done  at  once 
when  tuberculi)i  or  derivatives  of  tubercle  bacilli  are  employed 
in  those  cases  in  which  the  hyper-sensibility  conditions  are 
changed  for  the  worse  by  their  injection.  As  shown  above, 
an  undesirable  result  may  easily  be  brought  about  in  the 
treatment  with  tuberculin ;  we  do  not  as  yet  master  the 
conditions  of  hyper-sensibility  to  such  an  extent  that  they 
can  be  used  therapeutically  with  advantage. 

In  addition,  we  must  mention  that  the  newly-discovered 
local  reactions  can  also  be  employed  for  curative  purposes. 
Nagelschmidt  {Deutsche  rued.  Wochenschr.,  1907,  No.  40)  has 
employed  the  cutaneous  reaction  for  curative  purposes  in  cases 
of  local  tuberculosis  of  the  skin,  and  he  compares  the  results 
obtained  by  this  method  with  the  Finsen  treatment,  over 
which  it  has  the  advantage  of  being  universally  applicable  and 
cheaper.  On  the  place  of  application  a  strong  reaction  occurs 
which  may  lead  to  ulceration,  and,  healing  up,  forms  a  smooth 
scar.      So  also  Bandler  (Verein  D.A.  in  Prague,  Milnch.  med. 


140  THE  OPHTHALMIC  AND  CUTANEOUS 

Wochenschr.,  1907,  Ko.  52),  who  has  employed  ten  drops  of 
tubercuhn  locally  in  lapiis  witiiout  injurious  secondary  symp- 
toms. A  local  swelling  was  obtained,  the  little  lupus  nodules 
partly  ulcerated,  and  healed  up,  forming  a  smooth  scar. 

In  the  chapter  referring  to  ophthalmology  I  have  pointed 
out  the  possibility  of  apphnng  tuberculin  in  cases  of  ophthal- 
mic tuberculosis  for  therapeutic  purposes. 

Further  results  have  not  yet  come  in,  but  it  is  probable 
that  the  possibilities  for  the  therapeutic  application  of  the 
local  reactions  are  not  yet  exhausted.  When  objections  were 
made  with  regard  to  the  repeated  application  of  the  reaction  in 
the  Friedrichshain  Hospital,  I  expressed  the  conviction  that 
the  repeated  application  of  the  cutaneous  and  the  conjunctival 
reactions  represented  the  mildest  form  of  tuberculin  therapy, 
and  that,  if  the  tuberculin  therapy  was  at  all  justified,  the 
repeated  application  of  the  reaction  would  not  in  any  way 
injure  the  patient,  but,  on  the  other  hand,  might  be  of 
therapeutic  advantage. 

The  repeated  reactions  which  were  applied  to  the  same 
patients  caused  our  colleague,  Miinzer,  an  assistant  of  Pro- 
fessor Stadelmann  in  the  Friedrichshain  Hospital,  to  carry 
out  systematic  curative  experiments  with  repeated  cutaneous 
inoculations  in  patients,  based  on  the  view  that  in  this  way 
the  production  of  the  anti-substances  could  be  stimulated. 
Although  we  think  that  the  production  of  anti-substances  in 
the  sense  of  antitoxins  is  not  very  probable,  or  at  any  rate 
has  so  far  remained  without  any  proof,  yet  we  believe  that 
it  is  quite  possible  that  bacteriolysins  may  be  produced  ;  it 
certainly  is  a  good  idea  to  regard  the  process  of  the  produc- 
tion of  these  bacteriolysins  as  taking  place  in  an  altogether 
unaffected  tissue  at  some  distance  from  the  tubercular  centre. 
As  far  as  systematic  experiments  in  this  direction  are  con- 
cerned, which  only  after  a  long  time  can  give  reliable  results, 
I  should  like  herewith  to  ensure  Miinzer's  priority. 

Personally,  I  am  engaged  just  now  in  finding  a  practical 
therapeutic  application  of  the  percutaneous  introduction  of 
tuberculin  in  pulmonar}-  tuberculosis  and  in  lupus.  This 
method  represents  the  least  harmful  tuberculin  therapy  in 
existence  at  the  present  time. 


DIAGNOSIS    OF   TUBERCULOSIS  141 

THE  HISTORIC  DEVELOPMENT  OF  THE  DOCTRINE  OF  HYPER- 
SENSIBILITY,  OF  HYPER-SENSIBILITY  DISEASES,  OF  ALLERGY, 
AND    OF    THE    LOCAL    REACTIONS. 

The  local  tuberculin  reaction  has  not  been  invented  by 
accident,  so  to  speak,  but  a  long  history  is  attached  to  it.  Its 
discovery  only  became  possible  after  medical  attention  had 
been  directed  to  the  enormous  clinical  significance  of  the 
hyper-sensibility  phenomenon  by  the  works  of  Pirquet,  Schick, 
and  Wolff-Eisner.  First  of  all,  Richet  {Soc.  de  Biol.,  1902, 
p.  170,  1905,  21,  i.)  discovered  a  peculiar  substance,  to  be 
classified  with  the  medus£e  (actiniae),  the  injection  of  which 
did  not,  as  had  been  believed  for  a  long  time,  produce 
immunity,  but  left  the  body  in  a  state  of  hyper-sensibility. 
This  condition  was  called  anaphylaxia.  For  several  years 
this  was  the  only  case  on  record,  only  supplemented  by  the 
discovery  of  Arthus,  to  the  effect  that  repeated  injections 
with  the  serum  of  horses  brought  about  a  condition  of  hyper- 
sensibility.  Then  AVolff-Eisner,  after  numerous  experiments, 
put  the  doctrine  of  hyper-sensibility  on  a  broad  basis  and 
published  his  "  fundamental  law  of  immunitj',"  maintaining 
tJiat  the  injection  of  any  kind  of  albumin  (with  the  exception 
of  the  specially  characteristic  toxin)  produces  a  condition  of 
hijper-senslhllltij .  The  fundamental  principle  observed  by 
him  consisted  in  the  fact  that  all  kinds  of  albumin  behave 
in  exactly  the  same  way,  inducing  a  condition  of  hyper- 
sensibility,  whether  the  albumin  be  of  animal,  vegetable,  or 
bacterial  origin.  The  differences  between  the  various  kinds 
of  albumin,  according  to  him,  are  due  to  then*  purely  quanti- 
tative nature,  in  the  sense  that,  for  instance,  serum  albumin 
is  to  be  regarded  as  comparativelj'  harmless,  whereas  spernia 
albumin  is  poisonous  to  a  very  high  degree,  whilst  organ 
albumin  takes  a  place  between  these  two.  In  an  analogous 
way  he  differentiated  between  the  poisonous  character  of  the 
body  albumin  of  the  pathogenic  bacteria,  as  contrasted  witli 
the  comparatively  very  insignificant  poison  of  the  so  called 
saprophytes  {Zentralh.  f.  Bakt.,  vol.  87.). 

The  substantial  injections  of  albumin  substances  in  animals 
was  not  conducive  to  a  proper  study  of  the  clinical  conditions 
prevailing  in  cases  of  albumin  injections  ;  apart  from  all 
other  difficulties,  by  reason  of  the  fact  that  the  reactions  take 
so  rapid  a  course  that  sometimes  they  cause  the  death  of  the 
animal  within  a  few  minutes.  This  naturally  stands  in  the 
wav  of  thOroucrh  clinical  observation. 


142  THE  OPHTHALMIC  AND  CUTANEOUS 

Yet  this  work,  which  appeared  in  1904,  and  was  severely 
criticized,  and  which  proclaimed  hyper-sensi])ility  to  be  the 
general  principle  underlying  immunity,  constitutes  the  theo- 
retical basis  of  all  further  clinical  work  in  this  direction  (the 
creation  of  new  forms  of  disease). 

At  the  same  time  Pirquet  began  to  work  with  the  hyper- 
sensibility  reaction,  the  significance  of  which  (allergy)  he 
recognized  from  the  beginning,  and  for  which  he  is  entitled 
to  merit.  As  early  as  1902  he  published  a  work  on  incuba- 
tion. Those  who  will  take  the  trouble  to  compare  both  works 
will  be  convinced  of  the  absolute  independence  of  both  inves- 
tigators. To  put  it  concisely,  Pirquet  has  paid  most  attention 
to  the  local  symptoms  and  to  man,  whereas  Wolff-Eisner  was 
more  concerned  with  the  more  complicated  phenomena  of 
hyper-sensibility  in  animals.  This  way  of  putting  the  matter 
does  not,  of  course,  claim  to  express  the  idea  fully.  There  are 
a  good  many  important  points  upon  which  Pirquet  and  myself 
differ  greatly,  and  which  have  to  do  with  the  interpretation 
of  the  discoveries. 

On  the  basis  of  these  investigations  new  clinical  forms 
of  disease,  such  as  those  having  to  do  with  the  absorption  of 
foreign  albumin  substances,  were  formed  : — 

1903,  1904.     Serum  disease  (Pirquet  and  Schick). 
1905.     Hay  fever   (Wolff-Eisner)    and    Urticaria    (Wolff- 
Eisner). 
1907.     Re-vaccination  (Pirquet). 

In  the  case  of  serum  disease^  we  have  to  do  with  a  some- 
what natural  experimental  disease  which  occurs  after  the 
introduction  of  the  diphtheria  curative  serum,  as  a  rule 
obtained  from  horses,  the  clinical  appearances  of  which,  after 
the  injection  has  been  repeated,  produce  very  interesting 
changes  in  the  degree  of  rapidity  and  intensity  of  the  reaction, 
according  to  definite  rules.  Hay  fever,  on  the  other  hand, 
is  a  disease  which  occurs  spontaneously,  and  which  is  not 
caused  by  somewhat  experimental  measures,  and  as  such 
forms  the  prototype  so  far  of  a  clinical  form  of  disease  :  the 
hyper-sensibility  of  the  organism  with  regard  to  the  introduc- 
tion and  absorption  of  foreign  albumin  substance. - 

Both  these  hyper-sensibility  diseases — the  serum  disease 
and  hay  fever — have  been  studied  clinically  so  thoroughly  that 


'Von  Pirquet  u.  Schick,  "  Die  Serumkmnkheit,"  Deuticke,  Vienna,  1905. 
-  A.  Wolff-Eisner,  "  Das  Heufieber,'"  Lehniann,  Municli,  1906. 


DIAGNOSIS    OF   TUBERCULOSIS  143 

they  may  be  regarded  as  belonging  to  the  clinically  best  known 
forms  of  disease  (the  former  by  Pirquet  and  Schick,  the  latter 
by  Wolff-Eisner).  Let  me  point  out  here  that  the  historical 
representation  of  the  matter  by  Dorr  in  the  Wien.  klin. 
Wochenschr.,  1908,  No.  13,  gives  an  altogether  wrong  concep- 
tion of  the  actual  state  of  things. 

The  thorough  study  of  hyper-sensibility,  in  its  turn,  was 
conducive  to  a  better  understanding  of  the  processes  going  on 
in  cases  of  bacterial  infection.  As  observed  above,  Wolff- 
Eisner  based  his  investigations  on  the  analogous  conditions  of 
albumin  and  bacterial  albumin.  Hyper-sensibility  is  unfavour- 
able for  the  body  in  regard  to  albumin,  which  is  not  capable 
of  propagation.  Now  Pirquet  and  Wolff-Eisner  direct  our 
attention  to  the  fact  that  under  natural  conditions  the  harmful 
hyper-sensibility  of  the  body,  with  regard  to  albumin  substance 
which  has  no  propagating  capacity,  is  of  very  rare  occurrence. 
Much  more  frequent  is  the  hyper-sensibility  with  regard  to 
bacterial  infection,  and  in  this  case  it  has  all  the  significance 
of  an  extremely  important  reaction,  since  it  gives  a  stimulus 
to  the  mobilization  of  the  bacteriolytic  forces  of  the  body  (one 
of  the  active  factors  in  combating  infection). 

In  this  view  I  differ  to  some  extent  from  Pirquet,  who 
("  Serumkrankheit,"  p.  135))  regards  the  capacity  for  quicken- 
ing the  reaction  as  the  sole  form  of  immunity  in  cases  of 
chicken-pox,  variola,  measles,  German  measles,  whilst  I  attach 
to  it  a  general  significance,  at  the  same  time  also  believing 
it  to  play  a  part  in  bringing  about  bacteriolytic  immunity.  As 
regards  this  latter  point,  Pirquet,  in  his  work  on  re-vaccina- 
tion, has  approached  my  view,  being  induced  to  do  so  by 
an  absolutely  indisputable  proof  adduced  by  himself,  concern- 
ing the  simultaneous  appearance  of  vaccinations  applied  on 
different  days. 

Von  Pirquet  informs  me  by  letter  that  in  a  communication 
he  gave  in  the  early  part  of  1903  to  the  Academy  of  Sciences 
in  Vienna,  he  included  (besides  the  diseases  just  mentioned) 
relapsing  fever  and  the  repeated  injection  of  streptococci.  I 
have  not  seen  the  communication  referred  to  :  perhaps  it 
did  not  appear  in  print.  But  it  would  seem  as  if  Pirquet,  in 
190.5,  in  his  work  on  serum  disease,  had  again  reduced  the 
number  of  diseases  which  he  regards  as  coming  into  con- 
sideration in  respect  to  immunity  from  hyper-sensibility,  since 
here  he  appears  to  accept  other  conditions  as  governing  the 
bacterial  infections. 


144  THE  OPHTHALMIC  AND  CUTANEOUS 

In  my  publication  on  this  subject  iBerl.  kiln.  Wochenschr., 
1907,  No.  38)  I  pointed  to  the  fact  that  Pirquet's  newly- 
discovered  cutaneous,  as  also  my  own  conjunctival,  tuberculin 
reaction  represented  a  farther  proof  of  the  significance  of 
hyper-sensibility  in  the  case  of  immunity.  The  proofs — 
which  I  believe  to  be  absolutely  incontrovertible,  being  fur- 
nished by  the  reaction — I  have  treated  more  fully  in  the 
theoretical  part. 

It  w^as  especially  the  study  of  the  serum  disease  which 
induced  Pirquet  to  analyze  the  symptoms  occurring  in  re- 
vaccination  in  the  same  thoroughgoing  manner  from  a 
clinical  standpoint  as  also  from  that  of  the  immunity  doc- 
trine.-^ The  observations  made  on  this  occasion  were  the 
direct  cause  of  the  cutaneous  application  of  tuberculin  and 
of  the  entire  development  w'hich  follow^ed  this  discovery.  It 
took  place  in  the  following  manner :  In  re-vaccination  experi- 
ments he  observed  a  very  peculiar  condition  of  hyper-sensi- 
bility of  the  skin,  quite  similar  to  that  occurring  in  the  case 
of  tuberculosis  wuth  regard  to  tuberculin.  This  could  not 
have  been  foreseen,  because  in  the  case  of,  for  example,  hyper- 
sensibility  of  the  organism  to  pollen  albumin  the  hyper-sensi- 
bility does  )wt  affect  the  skin.  On  the  other  hand,  after 
this  cutaneous  hyper-sensibility  had  been  demonstrated  for 
tuberculosis  by  so  simple  an  experiment,  my  thoughts  tended 
in  the  direction  of  testing  the  sensibility  of  the  conjunctiva  to 
tuberculin  in  a  w^ay  which  would  be  analogous  to  that  pursued 
in  the  case  of  hay  fever. 

The  result  has  justified  the  experiment  ;  the  prevailing 
conditions,  however,  only  allow  of  a  result  in  cases  of  tuber- 
culosis and  allied  diseases.  It  was  due  to  these  conditions 
that  no  satisfactory  results  were  obtained  with  the  cutaneous 
and  the  conjunctival  reactions  in  typhoid  and  other  infectious 
diseases,  though  they  might  have  been  expected  according  to 
Pirquet's  theories,  which  I  regard  as  erroneous  ;  already 
some  years  ago  I  openly  declared  them  false.  On  account  of 
the  non-realization  of  Pirquet's  theories  on  the  matter,  outcry 
arose  also  against  regarding  the  local  tuberculin  reactions 
as  specific.  The  objections  raised  against  these  reactions  are 
based  upon  the  following  principles  : — 

(1)  That  tuberculous  individuals  do  not  react. 

(2)  That  diphtheria,  typhoid,  coli,  and  other  poisons  produce 


Von  Pirquet  u.  Schick,  "  Die  Seruiakrankheit,"  Deuticke,  Vienna,  1905. 


DIAGNOSIS    OF   TITHKRCULOSIS  J 45 

reactions  also  in  healthy  individuals,  and  tliat,  therefore,  such 
a  reaction  cannot  possibly  be  specific. 

Now  the  first  objection  also  holds  fi[ood  in  the  case  of  the 
subcutaneous  tuberculin  injection  ;  it  has  sufficiently  clearly 
been  dealt  with  in  the  course  of  this  work.  Klieneberger 
(Deutsche  med.  Wochenschr.,  April,  1908)  has  neither  troubled 
to  read  my  explanations  concerning  my  own  method,  which  he 
ventures  to  criticize,  nor  has  he  acquainted  himself— as  he 
might  have  done  even  without  studying  the  literature  to  any 
extent — with  the  fact  that  a  single  ophthalmic  instillation  of 
tuberculin  can  only  reasonably  be  compared  with  a  single 
subcutaneous  tuberculin  injection.  It  is  a  well-known  fact 
that  in  tuberculous  individuals  the  conjunctival  re-instilla- 
tion of  tuberculin  produced  IQQ  per  cent,  of  positive  reactions. 

I  will  not  further  trouble  the  English  reader  with  this 
matter,  which  is  merely  of  local  significance.  I  will  turn  now 
to  the  only  objection  raised  against  the  specific  nature  of  the 
reaction  which  can  seriously  be  discussed. 

It  is  obvious  that  a  toxin  like  that  of  the  diphtheria 
disease  produces  a  local  reaction,  the  poison,  when  bi'ought 
in  active  contact  with  the  skin,  exercising  a  toxic  action.  It 
is  different,  however,  with  the  endotoxin  substances  of 
typhoid  and  coli,  which  also  frequently  produce  a  reaction  in 
healthy  individuals.  These  endotoxin  substances,  to  become 
active,  must  first  be  liberated  from  the  bacteria  which  have 
been  introduced.  This,  as  we  know,  happens  by  the  aid  of 
bacteriolysin  substances,  and  these — as  has  been  demonstrated 
experimentally  (Pfeiffer's  experiment) — are  present  to  a  suffi- 
cient extent  with  regard  to  typhoid  and  coli.  It  is  therefore 
possible  that  in  the  healthy  individual  a  reaction  may  occur 
after  the  first  introduction,  increasing  the  difficulty  of  the 
diagnostic  application,  although  it  is  quite  possible  that  the 
more  exact  study  of  the  hyper-sensibility  conditions  in  infected 
individuals  may  also  in  this  case  prove  to  be  of  diagnostic 
advantage  ;  the  fact  that  the  reaction  occurs,  however,  does 
not  in  itself  allow  us  to  draw  diagnostic  conclusions. 

In  the  case  of  the  tubercle  bacillus  the  normal  bacterio- 
lysin substances  present  are  not  sufficient  to  effect  a  solution 
of  bacterial  substance,  which  can  occur  only  in  the  infected 
body  immunized  by  contact  with  the  bacteria.  This  fact  corre- 
sponds with  all  our  other  observations  concerning  the  lysis  of 
the  tubercle  bacillus,  proving  that  the  tuberculin  reactions 
are  characteristic  and  specific  for  tuberculous  individuals,  and 
10 


146  THE    OPHTHALMIC    AND    CUTANEOUS 

for  these  only.  The  different  kinds  of  reaction  have  their 
origin  in  the  different  forms  of  hyper-sensibiHty. 

Thus  it  was  simply  a  direct  transmission  of  experience 
gathered  whilst  studying  re-vaccination,  after  Pirquet  had 
to  some  extent  succeeded  in  localizing  the  tuberculin  reaction, 
with  one  blow  removing  all  disadvantages  which  are  attached 
to  the  subcutaneous  injection  of  tuberculin. 

{Added  during  Bevision. — I  must  insert  here  that  Max 
Wolff,  at  a  meeting  of  the  Berliner  Ophthalm.  Gesellschaft  on 
January  16,  1908,  as  also  in  an  article  in  the  Berl.  Idin.  Woch., 
January,  1908,  suggested  that  it  would  not  be  advisable  to 
revive  the  old  fairy  tale  concerning  the  injuriousness  of  the 
subcutaneous  tuberculin  injection.  One  cannot  discuss  so 
biassed  a  point  of  view.  If  he  reverts  to  authority  to 
maintain  this  standpoint,  we  can  adduce  more  numerous 
clinicians  of  probably  equal  authority  who  have  arrived  at 
different  conclusions  by  the  observation  of  clinical  material. 
Polyclinical  material  seems  to  me  to  be  inappropriate  for 
settling  the  question  concerning  the  subcutaneous  and  con- 
junctival reactions.) 

These  disadvantages  were  done  away  with  by  simply  intro- 
ducing minute  amounts  of  tuberculin  into  the  skin  (cuta- 
neously,  as  opposed  to  subcutaneously),  thus  forcing  the 
process  to  take  its  course  in  the  skin  itself.^     With  a  caution 

'  As  a  matter  of  fact,  the  first  cutaneous  reaction  was  obtained 
by  the  well-known  dermatologist  KUngmiiller,  and  by  Escherich,  who 
would  have  been  the  discoverer  of  the  cutaneous  reaction  had  he  not 
proceeded  from  an  erroneous  tlieoretical  basis.  He  was  of  opinion  that 
the  reaction  in  question  could  only  be  obtained  in  individuals  with  distinct 
manifestations  of  cutaneous  tuberculosis.  Otherwise  Klingmitller  ought 
to  have  been  the  discoverer  of  the  cutaneous  reaction,  in  the  same  way 
as  the  ophthalmologist  ought  to  have  discovered  the  conjunctival  reaction. 
The  puncture  reaction  would  not  have  been  forgotten  even  without  Pirquet's 
interference,  since  Dely  employed  the  puncture  reaction  for  differential 
diagnostic  purposes,  and  Hamburger,  at  the  same  hospital  as  Pirquet, 
carried  out  extensive  experiments  with  puncture  reactions.  For  this  reason 
it  is  remarkable  that  Pirquet  has  never  referred  to  the  cutaneous  puncture 
reaction  and  its  close  relationship  with  his  cutaneous  reaction. 

As  mentioned  before,  Pirquet  had  communicated  his  discoveries  to 
me,  and  already  on  May  15  I  was  able,  in  conjunction  with  Baginsky, 
to  confirm  the  results  of  his  observations. 

My  publications  concerning  hyper-sensibility,  and  especially  my  experi- 
ences in  cases  of  hay  fever,  caused  me  to  employ  tuberculin  for  diagnostic 
purposes.  On  May  15  I  had  already  a  fairly  large  amount  of  material 
at    my  disposal   (more  than   100  cases)  which  had  been   treated  conjunc- 


DIAGNOSIS   OP   TUBERCULOSIS  147 

in  harmony  with  the  difficult  material  in  hand  I  maintained 
that  further  conclusions  could  onl}^  be  arrived  at  after  the 
investigation  of  a  very  large  amount  of  material,  the  more  so 
since  Pirquet,  in  making  a  diagnostic  use  of  his  cutaneous  re- 
action, had  advised  caution  in  treating  adults,  whilst  at  the 
same  time  I  was  enabled  to  observe  that  differences  exist 
between  the  cutaneous  and  the  conjunctival  reaction,  the  full 
explanation  of  which  was  not  as  3'et  forthcoming. 

Calmette  only  began  to  experiment  after  Pirquet's  publication — 
towards  the  end  of  May — and  published  bis  experiments  on  June  17, 
as  the  "  ophthalmic  reaction "  (Acad,  des  Sciences)  ;  at  the  same  time  he 
puts  my  publication  down  to  June  3,  thus  approaching  the  period  of  his  own 
publication,  which  is  not  consistent  with  the  actual  facts.  We  have  at 
other  places  referred  to  Calmette's  tuberculin  test,  Ike. 

It  is  due  to  Calmette's  work  that  the  reaction  has  been 
so  rapidly  introduced  into  clinical  practice.  It  is  an  abso- 
lutely untenable  assertion  to  maintain  that  I  had  not  made 
clinical  use  of  this  method,  and  had  not  recommended  it  for 
clinical  purposes.  (See  Petit,  p.  26  :  "  Wolff-Eisner  declarait 
du  reste,  a  ce  moment,  ne  rien  pouvoir  aftirmer  au  sujet  de  sa 
valeur  diagnostique,  n'ayant  pas  encore  experimente  cette 
methode.")  The  second  part  of  the  sentence  is  altogether  beside 
the  truth,  the  first  part  distorted.  A  communication  still  less 
consistent  with  the  truth  of  the  matter  has  been  given  by 
Citron  at  the  meeting  of  the  Berliner  Ophthalin.  Gesellschaft 
of  January  16,  1908.  I  refer  to  to  the  report  of  the  meeting 
in  question  in  the  Bed.  hlin.  Wochenschr.,  1908,  and  my  final 


tivally  with  10  per  cent,  tuberculin.     I  declared  the  reaction  to  be  specific, 
and  assigned  to  it  a  diagnostic  and  prognostic  significance. 

I  will  explain  here  in  a  very  few  words  how  my  experiments  with  hay 
fever  induced  me  to  at  once  apply  tuberculin  to  the  conjunctiva,  as 
soon  as  I  had  heard  of  the  cutaneous  reaction.  In  disagreement  with 
Dunbar,  I  represent  the  view  that  in  hay  fever  we  have  not  to  do  with 
the  action  of  toxic  substances,  but  with  that  of  a  poison  of  an  albuminous 
character.  The  poisons,  under  the  action  of  lytic  substances,  are 
liberated  from  the  pollen.  Therefore,  in  order  that  hay  fever  symptoms 
should  appear,  it  is  necessary : — 

(1)  That  lytic  substances  should  be  present,  quickening  the  absorption 
by  liberating  the  poison  (present  in  all  hay  fever  patients). 

(2)  That  there  should  be  hyper-sensibilit\-,  which  is  produced  for 
pollen  albumin  in  the  same  way  as  for  all  other  albuminous  substances. 
The  hyper-sensibility  differs  quantitatively  in  each  case  of  pollen-sensi- 
bility. 

This  co7iception  of  haij  fever  enabled  me  to  at  once  transmit  the 
conjunctival  reaction  ivith  tuhercuUn  to  tuberculosis. 


148  THE  OPHTHALMIC  AND  CUTANEOUS 

reply  in  the  Ver.  f.  inn.  Med.,  January,  1908.  Calmette 
started  his  experiments  after  having  read  the  results  obtained 
by  Pirquet  ("  aussitot  qu'il  eut  connaissance  de  son  [Pirquet's] 
premier  travail").  Since  I  published  my  conjunctival  reaction 
together  and  in  the  same  paper  with  Pirquet's  cutaneous 
reaction,  Calmette  ought  to  have  had  knowledge  of  the 
method,  as  also  Valiee,  who  on  the  very  same  day  com- 
municated to  the  Acad,  des  Sciences  of  Paris  his  application 
of  the  conjunctival  reaction  in  oxen. 

Calmette  maintains  he  has  discovered  the  ophthalmic  re- 
action independently  of  me  ;  but  even  in  this  case  I  have  the 
undoubted  right  of  priority,  and  at  any  rate  the  same  right 
as  Calmette,  quite  apart  from  the  role  I  have  played  in 
developing  the  reaction  practically  and  theoretically. 

THE    OUTLOOK. 

The  fact  that  a  great  number  of  healthy  individuals  react 
to  tuberculin — that  is  to  say,  show  hyper-sensibility  with 
regard  to  tubercle  bacilli  derivatives,  whicb,  according  to  our 
view,  in  the  case  of  re-infection  makes  it  easier  to  combat  the 
new  infection — causes  us  to  critically  review  the  measures 
taken  in  reference  to  tuberculosis  prophylaxis.  Modern 
prophylaxis  endeavours  to  prevent  infection  by  keeping  the 
tubercle  bacilli  at  bay.  Parallel  to  this  we  have  the  attempts 
to  produce  active  and  passive  immunization,  and  to  eliminate, 
if  possible,  the  diseased  individuals  in  order  to  obtain  by  selec- 
tion a  race  free  from  tuberculosis.  We  can  pass  over  the 
active  and  passive  immunization  in  a  few  words,  since  the 
attempts  in  this  direction  have  so  far  been  without  any 
remarkable  results  (see  Eber,  79,  Naturforschervers.  ref.  intern. 
Zentralh.  f.  Tuberk.,  1907,  p.  115).  In  the  human  race  a 
natural  selection  must  take  place  by  the  dying  off  of  tuber- 
culous families,  if  only  partially.  In  the  case  of  cattle- 
breeding  such  endeavours  can  be  carried  out  on  a  larger  scale. 

Thus,  as  mentioned  above,  the  prophylaxis  as  far  as  man 
is  concerned  can  only  consist  in  attempts  to  diminish  the 
chance  of  infection.  This  is  done  by  retaining  the  sputum, 
and  by  teaching  hygiene  in  sanatoria  and  hospitals,  showing 
the  patient  how  to  deal  with  his  sputum,  &c.  It  cannot  be 
denied  that  in  this  way  a  great  deal  of  good  has  been  done, 
since  some  of  the  patients  bring  out  such  an  enormous 
number  of  bacilli  that  even  the  men  with  the  most  resistance 


DIAGNOSIS    OF    TUBERCULOSIS  149 

cannot  withstand  an  infection  of  this  sort,  and  from  this 
point  of  view  we  can  only  welcome  the  prohibition  to  spit 
in  waiting-rooms,  railway  carriages,  and  other  public  places. 
As  a  matter  of  fact,  it  would  be  a  highly  desirable  measure 
to  absolutely  prohibit  spitting  in  all  public  buildings  and  resi- 
dences. I  make  a  special  point  of  these  things  in  order  to 
avoid  the  misconception  that  I  pooh-pooh  these  hygienic 
principles,  because  I  really  doubt  whether  the  decrease  of 
tuberculosis  observed  in  recent  years  is  to  he  attributed  to 
these  measures.  If  we  consider  that  the  immunity  of  man, 
that  is  to  say  the  absence  of  active  progressive  tuberculosis 
in  most  people,  depends  on  an  increase  in  the  reactive  capacity, 
i.e.,  on  a  state  of  hyper-sensibility,  it  would  seem  to  us  that 
if  man  no  longer  encountered  tubercle  bacilli  a  race  would 
appear  which  would  at  once  succumb  to  such  an  encounter. 
Veterinary  scientists  have  frequently  observed  this  condition 
of  things  in  uninfected  animal  bodies,  and  also  in  man  such 
states  have  been  met  with.  One  might  mention  measles  in 
the  case  of  the  Faroe  Islanders.  We  will  confine  ourselves, 
however,  to  tuberculosis.  The  negro,  for  instance,  does  not 
meet  with  tubercle  bacilli  in  Africa,  and  therefore  in  his 
native  land  he  is  free  from  tuberculosis  ;  in  other  parts  of 
tlie  world,  however,  he  exhibits  an  extraordinary  tendency 
to  contract  tuberculosis.  Ziemann  himself,  who  is  one  of 
the  best  authorities  on  Africa,  assured  me  that  this  was 
actually  due  to  the  fact  that  the  negro  in  Africa  does  not  come 
in  contact  with  tubercle  bacilli.  Ziemann  has  never  found 
tuberculosis  in  cattle  in  Africa,  and  altogether  only  one  case 
of  tuberculosis  in  a  fowl  ;  he  has  also  observed  that,  as  soon 
as  there  is  a  tuberculous  European  living  in  Africa,  the 
negroes  living  in  his  vicinity  very  easily  take  up  the  tubercle 
bacilh. 

The  hygienic  measures  for  destroying  the  sputum  contain- 
ing the  tubercle  bacilli  are  very  justifiable ;  every  civilized 
man  has  sufficient  opportunity  to  meet  with  tubercle  bacilli 
in  other  ways,  to  overcome  them,  and  to  establish  a  relative 
immunity  with  regard  to  tuberculosis  with  hyper-sensibility. 
Thus  if  we  see  that  numerous  people  possess  latent  centres 
which  may  become  active  under  certain  conditions  of  life, 
and  if  at  the  same  time  we  consider  that  an  infection  with 
tubercle  bacilli  can  only  be  overcome  if  the  outer  conditions 
are  very  favourable,  we  find  that  it  is  necessary — without 
depreciating    the    hygienic    measures   taken   to   decrease   the 


150  THE  OPHTHALMIC  AND  CUTANEOUS 

danger  of  infection — to  provide  hygienic  conditions  of  life  in 
order  to  combat  and  put  an  end  to  tuberculosis  as  a  disease 
of  the  people  :  good  air,  good  food,  good  housing.  Especially 
the  hygiene  of  the  work  contemplated  has  to  be  developed ; 
this  has  been  maintained  for  a  long  time  past  by  all  practical 
hygienists  in  combatmg  tuberculosis.  Of  all  these  hygienic 
problems  the  one  concerning  diet,  in  a  sense,  is  the  factor  which 
it  IS  easiest  to  regulate  and  enforce.  I  regard  the  problem 
of  popular  diet  as  one  of  the  chief  factors  in  the  battle  against 
tuberculosis.  Since,  under  the  prevailing  conditions  in  Ger- 
many, this  question  is  not  merely  one  of  hygiene,  but  at  the 
same  time  one  of  politics,  I  will  content  myself  with  this 
reference. 

Thus  the  well-known  saying  of  Grancher  becomes  quite 
intelligible  from  the  scientific  point  of  view:  "Each  country 
combats  tuberculosis  in  its  own  way ;  Germany  by  means 
of  sanatoria,  England  with  beefsteak  and  tennis.  Personally 
I  prefer  the  English  method  ;  it  is  more  pleasant  and  more 
efficacious."  (Quoted  from  the  Deutsche  vied.  Wochenschr., 
No.  40,  1907;  Schober,  Paris  letter.) 


The  methods  allow  of  a  broad  outlook  also  from  a  scientific 
point  of  view.  One  of  the  most  important  theoretical  ques- 
tions touched  by  these  investigations  we  have  dealt  with  in 
the  course  of  this  work.  A  perfect  solution  of  these  problems 
has  not  been  expected  up  to  the  present  ;  further  investiga- 
tion will  bring  about  unexpected  results.  But  these  problems 
which  we  have  been  discussing  to  some  extent  do  not  by 
any  means  represent  all  scientific  aspects  which  will  be 
elucidated  by  this  reaction,  and  clear  up  most  questions  of 
long  standing.  We  will  discuss  the  question  of  congenital 
infection  with  tuberculosis  in  this  outlook,  because  we  are 
entirely  dependent  in  this  respect  on  statements  in  the 
literature  on  the  subject,  we  ourselves  not  having  been  able 
to  experiment  on  children  and  infant  material.^ 

After  autopsies  in  children  the  problem  concerning  the 
occurrence  of  the  congenital  infection  with  tuberculosis  turned 
against  Baumgarten's  views,  and  even  Friednch  Franz  Fried- 
mann  could  only  prove  the  ^possibility  of  the  occurrence  of 

'  Dr.  Julius  Eitter  has  promised  to  carry  out  experiments  in  his  infant 
home  with  the  cutaneous  and  conjunctival  reactions  simultaneously  applied, 
and  will  communicate  on  the  subject  before  long. 


DIAGNOSIS    OF   TUBERCULOSIS  151 

congenital  tuberculous  infection  under  very  special  experi- 
mental conditions.  The  results  of  the  reaction  may  be 
regarded  as  settling  this  question,  by  showing  that  for  prac- 
tical purposes  the  occurrence  of  a  congenital  infection  is 
to  be  ignored. 

Prouff,  Bue,  Sonneville  (Petit,  p.  75)  together  have 
applied  the  method  to  fifty-seven  newly  born  infants  and  have 
not  once  obtained  a  positive  conjunctival  reaction,  although 
fifteen  of  the  mothers  had  given  a  positive  reaction. 

The  results  obtained  with  the  reaction  throw  interesting 
side-lights  on  the  well-known  and  controversial  theory  of 
Behring,  to  the  effect  that  in  infancy  tubercle  bacilli  are  taken 
up  by  the  intestine  of  the  infant  which  is  accessible  to  the 
bacillus,  and  after  having  been  latent  for  years  may  cause  an 
outbreak  of  tuberculosis  and  consumption.  This  remarkable 
theory  had  no  definite  clinical  basis  ;  it  has  not  been  proved 
that  children  who  in  infancy  received  any  nourishment  con- 
taining tubercle  bacilli,  being  fed  with  mother's  milk  (from 
healthy  mothers)  or  cow's  milk  boiled,  showed  any  great 
difference  from  children  fed  in  any  other  manner.  In  reference 
to  this  theory  the  result  of  the  reaction  proves  that  as  a  rule 
no  tuberculosis — not  even  a  latent  one — is  produced  during 
the  infant  stage,  and  also  shows  the  correctness  of  the  pedia- 
trists'  view  that  tuberculosis  contracted  during  early  childhood 
always  indicates  death,  and  never  a  latent  centre. 

On  the  other  hand,  however,  the  reaction  has  shown  that 
Behring  was  right  when  maintaining  that  in  an  exceedingly 
large  number  of  individuals  tuberculosis  is  present  in  a  latent 
condition.  (This  could  only  be  demonstrated  by  a  form  of  the 
reaction  which  only  showed  that  latent  centres  were  present. 
Bee  our  earlier  chapters.) 

After  the  well-known  post-mortem  results  these  facts  might 
have  found  us  more  prepared,  but  we  must  not  lose  sight  of 
the  different  impressions  produced  by  finding  old  tubercular 
centres  on  autopsy,  and  by  finding  latent  centres  m  living 
people  who  had  so  far  been  regarded  as  perfectly  healthy, 
and  perhaps  even  in  ourselves.  Clinical  importance  is  attached 
only  to  latent  tuberculosis  in  the  living  individual,  not  to 
the  post-mortem  result. 

It  is  likely  that  the  reaction  may,  at  all  events  to  some 
extent,  decide  the  question  concerning  the  difference  between 
bovine  and  human  tuberculosis,  if  only  after  the  most  preci;ie 
representation  of  the  observations  made  in  the  shape  of  curves. 


152  THE  OPHTHALMIC  AND  CUTANEOUS 

It  is  to  be  foreseen  that  both  kinds  of  bacteria  possess  ingre- 
dients in  common  (see  Detre  and  Levy,  Orvosi  Hetilap,  1907, 
No.  46),  so  that  human  tuberculosis  will  give  a  reaction  on 
bovine  tuberculosis  and  vice  versa.  AVhen,  by  the  application 
of  our  curve  method,  we  shall  at  last  be  able  to  distinguish 
between  human  and  bovine  tuberculosis,  the  reaction  would 
enable  us  to  obtain  a  large  amount  of  material  concerning 
the  number  and  kind  of  bovine  infection,  and  to  decide  the 
question  to  what  extent  infection  occurs  with  bovine  tuber- 
culosis by  drinking  cow's  milk  unboiled.  (See  also  the  chapter 
on  the  Differentiating  Cutaneous  Reaction.) 

Thus  we  see  that  the  application  of  the  reaction  provides 
a  large  field  of  scientific  investigation,  and  promises  even 
more.  The  solution  of  scientific  problems  is  directly  or  in- 
directly connected  with  practical  results.  The  application 
of  the  reaction  in  practice  is  of  still  greater  practical  utility. 
First  of  all  a  golden  rule  is  brought  home  to  us  by  the  reaction, 
a  rule  which,  from  the  point  of  view  of  the  medical  man  and 
the  national  economist,  can  hardly  be  emphasized  suhiciently  ; 
the  so-called  receptive  individuals  in  reality  are  tuberculous 
already,  and  are  such  persons  as  are  combating  tuberculosis. 
Tbe  German  language  [or  the  English,  for  that  matter — 
Translator]  is  hardly  pliable  epough  to  reproduce  the  neatness 
of  Calmette-Petit's  way  of  putting  the  matter.  "  Les  pre- 
disposes sont  les  tuberculeux  et  non  les  tuberculisables." 
Calmette  (Petit,  p.  120)  gives  a  splendid  representation  of 
the  action  of  the  generally  employed  local  reaction.  It  is  too 
tempting  a  passage  not  to  be  given  here  in  full : — 

"  On  comprend  tout  de  suite  I'interet  qu'offre  une  methode 
aussi  simple  et  aussi  sure  pour  depister  la  contagion  tubercu- 
leuse  dans  les  families. 

"  Actuellement,  lorsqu'un  medecin  est  appele  a  donner  ses 
soins  a  un  malade,  a  quelque  classe  sociale  que  ce  dernier 
appartienne,  s'il  reste  entoure  des  siens,  il  est  extremement 
diihcile,  pour  ne  pas  dire  impossible,  d'eviter  a  son  entourage 
toutes  les  occasions  de  contagion.  Tot  ou  tard,  celle-ci,  quoi 
([n'on  fasse,  trouverait  a  s'exercer,  soit  par  le  linge,  soit  par 
les  particules  salivaires  emises  pendant  la  toux,  soit  par  les 
mains  ou  par  les  aliments  souilles  de  bacilles. 

"  Les  enfants  y  sont  plus  particuHerement  exposes  a  cause 
de  leur  insouciance  et  de  leur  ignorance  du  danger.  Comment 
reconnaitre  chez  eux  le  debut  d'une  infection  qui  peut  rester 
latente  pendant  des  annees,  ou  qui  ne  s'aggravera  bientot 
qu'a  la  faveur  de  reinfections  successives  et  multiples  ? 


DIAGNOSIS   OF   TUBERCULOSIS  153 

"  Sans  doute,  dans  quelques  cas,  f^race  ci  une  surveillance 
etroite  et  a  I'eniploi  judicieux  de  la  methode  d'auscultation 
fine  de  Grancher,  on  reussira  a  saisir  les  premieres  manifesta- 
tions apparentes  du  mal.  Mais  les  desordres  organiques 
seront  alors  trop  souvent  irremediables. 

"  L'ophtalmo-reaction,  periodiquemenL  essayee  sur  cbacun 
des  membres  de  la  famille,  peut  trouver  ici  son  application 
la  plus  utile  peut-etre  et  la  plus  feconde.  Elle  donne  au 
medecin  le  moyen  de  s'eclairer  ;  elle  lui  fournit  le  meilleur 
des  arguments  pour  exiger,  soit  I'isolement  du  malade,  soit, 
lorsqu'il  en  est  temps  encore,  I'envoi  a  la  campagne  ou  le 
placement  en  sanatorium  de  ceux  des  siens  qu'il  a  deja 
contamines. 

"  Tous  ceux  d'entre  nous  qui  s'occupent  de  lutte  sociale 
antituberculeuse  sentent,  combien  la  nouvelle  metbode  de 
diagnostic  precoce  dont  il  s'agit,  va  leur  etre  precieuse  pour 
selectionner  ces  enfants,  nes  de  parents  tuberculeux,  mais 
encore  sains  eux-memes,  qu'il  est  si  urgent  de  soustraire  a  la 
contagion,  en  les  placant  a  la  campagne  chez  les  paysans 
indemnes  de  toute  tare  !  Topbtalmo-rcaction  foumira,  a  cette 
oeuvre  admirable  fondee  par  le  regrettc  Grancher,  ce  qui  lu, 
manquait  :  elle  lui  permettra  d'affirmer  la  non-existence  de 
lesions  tuberculeuses  chez  ses  pupilles.  Elle  permettra  auss, 
de  diriger  tout  de  suite  vers  les  sanatoriums  marins  ou  vers 
1  etablissement  d'Ormesson  les  jeunes  enfants  chez  lesquels 
elle  aura  revele  I'existence  de  lesions  latentes  ou  insoupconnees 
cliniquement.  On  comprend  sans  peine  I'immense  benefice 
social  qui  resultera  forcement  de  la  promptitude  avec  laquelle 
des  soins  eclaires  les  entoureront !  " 

Also  these  apparently  extravagant  hopes  will  be  fulfilled 
as  soon  as  humanity  shall  be  able  to  afford  the  financial  cost 
of  actively  combating  tuberculosis.  The  correct  interpreta- 
tion of  the  reaction  holds  out  a  possibility  of  an  early  diagnosis 
to  an  extent  never  before  conceived,  and  therefore  also  the 
possibility  of  successes  never  before  attained.  It  is  hardly  a 
point  of  discussion  nowadays  that  the  cure  of  tuberculosis 
depends  on  tbe  early  diagnosis  of  the  disease,  and  that  the 
comparatively  unsuccessful  results  obtained  in  the  sanatoria 
are  due  to  the  fact  that  obvious  cases  of  tuberculosis,  wbich  are 
indicated  by  the  appearance  of  tubercle  bacilli  in  the  sputum, 
can  only  very  rarely  be  cured.  But  there  is  no  doubt  that, 
when  properly  managed,  the  sanatoria  can  still  be  of  very 
great    use   in    combating    tuberculosis.      One  must,   however. 


154  THE  OPHTHALMIC  AND  CUTANEOUS 

make  up  one's  mind  to  admit  all  individuals  giving  a  positive 
reaction  into  the  sanatoria,  even  if  no  clinical  symptoms  of 
any  description  be  found.  The  specific  reaction  indicates 
the  presence  of  tuberculosis  in  the  body,  which  may  be 
cured  with  practical  certainty  if  the  individual  in  question 
is  provided  with  favourable  external  conditions. 

Already  nearly  every  hospital  patient  is  examined  by 
means  of  the  local  reactions.  We  may  predict  a  time  in 
which  the  reaction  will  accompany  man  through  life.  In  the 
schools  the  reacting  pupils  will  be  isolated,  and  brought  to 
forest  schools,  and  sanatoria,  and  especially  to  sea  hospitals  ; 
thus  will  tuberculosis  be  combated  in  the  schools.  It  will 
play  a  part  in  industrial  hygiene,  and  it  will  also  give  im- 
portant results  in  the  army,  indicating  the  distribution  of 
tuberculosis  among  the  people  generally,  at  the  same  time 
preventing  tuberculous  individuals  from  entering  the  army 
or  the  navy.  In  this  way  tuberculosis  may  be  further  com- 
bated in  the  army,  although  to  some  extent  this  occurs  already 
by  means  of  the  prevailing  measures.  The  renewed  applica- 
tion of  the  reaction  when  the  soldier  leaves  the  ranks  will 
show  whether  tuberculosis  has  made  its  appearance  during 
military  service. 

The  splendid  medical  organization  of  the  German  Army 
has  already  frequently — for  purposes  of  combating  epidemics, 
— made  use  of  a  remark  emphasized  by  Schjerning  in  his 
opening  speech  to  the  last  Congress  on  Hygiene.  The  same 
organization  can  be  of  the  greatest  value  by  simply  handing 
the  results  of  the  reaction,  together  with  the  clinical  con- 
dition, to  the  civil  registrars  and  hospital  authorities  in  a 
manner  which  has  been  recently  recommended  by  Pannwitz 
at  the  fourth  Conference  of  Tuberculosis  Specialists  at  Berlin. 

Objections  have  been  raised  against  the  application  of  the 
reaction,  to  the  effect  that  the  very  sensitive  cutaneous 
reaction  would  cause  fear  of  tuberculosis  with  every  little 
cold  or  ailment,  and  that  hypochondria  would  be  more 
prevalent  than  ever.  I  regret  to  say  that  notions  of  that 
sort  have  even  appeared  in  newspapers  and  have  remained 
uncontradicted,  since  I  did  not  regard  the  daily  press  as  an 
appropriate  medium  for  the  discussion  of  scientific  problems. 

Such  objections  I  do  not  regard  as  reasonable,  since  the 
same  might  be  maintained  with  reference  to  the  publication 
of  Nageli's  statistics  concerning  the  distribution  of  tuber- 
culosis.    If  it  becomes  common  knowledge  that  most  human 


DIAGNOSIS   OF   TUBERCULOSIS  155 

beings  have  successfully  resisted  tuberculous  infection,  the 
recognition  of  this  fact  would  not  by  any  means  produce  a 
genev&l  fear  of  tuberculosis,  but  would  rather  tend  to  put  into 
the  proper  light  the  advantages  of  taking  hygienic  measures. 

Bliimel  and  Clarus  reply  to  these  fears  that  they  cannot 
at  any  rate  be  applicable  to  the  cutaneous  reaction,  since  it 
is  not  more  sensitive  than  the  subcutaneous  injection  method. 
At  the  same  time  it  would  seem,  they  say,  as  if  the  public — 
medical  as  well  as  lay — had  become  more  optimistic  with 
regard  to  pulmonary  tuberculosis.  They  were  in  a  position 
to  judge,  being  doctors  in  sanatoria  (in  Gobersdorf),  and  could 
enumerate  a  good  many  examples.  This  optimism  is,  at  all 
events,  just  as  significant  as  the  pessimism  which  formerly 
prevailed,  when  every  lung  patient  was  regarded  as  a  death 
candidate. 

The  importance  of  the  reaction  to  life  insurance  com- 
panies for  forming  diagnostic  and  prognostic  opinions  is  too 
evident  to  need  further  consideration  on  my  part. 

The  reaction  becomes  of  very  great  importance  when  we 
come  to  deal  with  the  gravest  problem  of  prison  hygiene, 
viz.,  that  concerning  prison  tuberculosis.  The  well-known  fact 
that  so  very  many  cases  of  tuberculosis  occurred  in  prison  was 
very  puzzling  :  it  was  hardly  conceivable  that  the  infection 
with  tubercle  bacilli  could  have  taken  place  in  the  prison 
itself.  Our  discoveries  concerning  the  extremely  frequent 
occurrence  of  latent  tuberculosis  at  once  throw  light  on 
this  problem.  Under  the  influence  of  mental  depression,  the 
latent  tuberculosis  becomes  patent  and  acute.  It  would  be 
of  very  great  value  if  prison  doctors  applied  the  reaction 
to  the  prisoners  on  their  arrival,  and  every  six  months  after- 
wards. Such  a  course  of  action  would  still  more  decidedly 
prove  the  accuracy  of  our  theories,  and  the  influence  of 
external  conditions  on  the  course  of  the  tuberculosis.  In  any 
case,  it  would  lead  to  an  improvement  in  prison  hygiene, 
which  is  often  regarded  as  being  already  far  too  good  as  it  is. 

THE    CLINICAL    METHODS    OF    EARLY   DIAGNOSIS. 

The  Sputum  Investigation. 

Since  the  discovery  by  Koch  of  the  tubercle  bacillus  in 
1882,  the  presence  of  tubercle  bacilli  in  the  sputum  has 
been  regarded  as  the  deciding  symptom,  not  only  in  the  case 
of  sputum  investigation,  but  generally  in  the  examination  of 


156  THE  OPHTHALMIC  AND  CUTANEOUS 

incipient  pulmonary  tuberculosis.  We  have  already  men- 
tioned that  the  importance  of  the  tubercle  bacillus  is  not  so 
gi'eat  as  was  originally  suspected,  since  its  presence  does  not 
indicate  the  very  early  cases. 

The  Part  Played  by  the  Tubercle  Bacillus  in  Early  Dia- 
gnosis.— The  importance  of  the  tubercle  bacillus  for  the 
purpose  of  an  early  diagnosis  of  tuberculosis  has  become  so 
small  that  it  would  seem  advisable,  as  an  antithesis  to  its 
under-valuation,  to  point  to  the  extremely  great  significance  of 
the  tubercle  bacillus  even  for  the  purposes  of  early  diagnosis, 
and,  at  any  rate,  to  call  attention  to  the  facts  recognized  by  all 
those  who  have  a  large  amount  of  material  at  their  disposal  in 
which  tubercle  bacilli  are  to  be  found  ;  although  it  must  be 
confessed  that,  notwithstanding  all  experiments  in  this  direc- 
tion, physical  examination  has  not  produced  any  distinct 
results,  quite  apart  from  the  fact  that  for  the  numerous 
general  clinicians  who,  by  their  great  amount  of  work  along 
surgical  and  gynaecological  lines,  do  not  master  the  finest 
methods  of  percussion  to  the  greatest  extent,  the  discovery 
of  tubercle  bacilli  will  always  remain  an  important  comple- 
ment to  their  diagnosis,  which  not  even  the  discoverer  of  the 
apical  percussion  would  think  it  safe  to  do  without. 

Technique. — The  acid-resisting  properties  of  the  tubercle 
bacilli  were  long  regarded  as  absolutely  characteristic.  This 
view  cannot  any  longer  be  maintained,  since  numerous  other 
acid-resisting  bacteria  have  become  known  (Eabinowitsch, 
Deutsche  med.  Wochenschr.,  1900,  No.  16),  which  may  some- 
times be  present  in  the  lungs,  or,  according  to  A.  Frankel, 
("Diseases  of  the  Lungs"),  Milchner,  and  others,  in  the 
bronchial  cavities.  However,  this  discovery  seems  to  be  so 
rare  that  it  may  be  ignored  for  all  practical  purposes.  As  far 
as  the  technique  itself  is  concerned,  I  recommend  the  method 
of  Baumgarten ;  that  of  Gabbet  I  regard  as  less  appro- 
priate, since  the  distance  cannot  be  controlled,  and  also 
because  the  method  of  Baumgarten  enables  us  to  separate 
a  part  of  the  acid-resisting  bacteria  (smegma)  from  the 
tubercle  bacilli  by  means  of  the  2  per  cent,  hydrochloric  acid 
alcoholic  solution  for  removing  the  stain  (A.  Pappenheim, 
Berl.  klin.   Wochenschr.,  1898,  No.  87). 

Staining  MetJtods  of  Kronig. — Kronig  has  recently  (Mediz. 
Klinik.,  1907,  No.  24,  Deutsche  Klinik,  1907)  recommended 
a  method  for  staining  the  sputum,  which  he  regards  as  pro- 
ducing   the   maximum    amount    of   staining.      It    consists   in 


!)IAGNOSIS    OF   TUBERCULOSIS  157 

heatin^^  the  carbolic  fuchsin  not  only  to  evaporation,  but 
allowing  it  to  boil  up  several  times,  in  exactly  the  same  way 
as  is  done  in  staining  spores.  He  recommends  the  use  of 
a  special  apparatus  in  which  the  boiling  may  take  place. 
The  result  is  a  thickening  of  the  tubercle  bacilli  as  usually  seen 
under  the  microscope.  He  maintains  that  the  principal  object, 
the  increase  of  the  acid-resisting  capacity  in  the  tubercle 
bacilli,  is  attained  by  this  method.  The  acid-resisting  capacity 
of  the  spores  frequently  remains  comparatively  small,  notwith- 
standing maximum  staining.  To  those  who  have  some  diffi- 
culty in  observing  the  tubercle  bacilli  by  reason  of  their 
thinness,  this  method   will  be  an  invaluable  acquisition. 

Magnifying  Dish  of  Kronig. — I  heartily  recommend  the 
so-called  magnifying  dish  of  Kronig  (p.  fjlO  of  the  DeidscJie 
Klinik,  I.e.).  It  consists  of  a  glass  dish  which  is  divided  into 
three  sections  of  different  transparency  (black,  milky-opaque, 
and  glass),  and  a  mirror  which,  in  a  microscope,  has  a  light 
underneath.  This  dish  assists  considera])ly  in  finding  those 
particles  in  tlie  spiituiii  in  which  the  tubercle  l)acilli  are  most 
likely  to  be  contained. 

Furthermore,  it  is  of  importance  to  know  how,  if  there  is 
no  sputum,  appropriate  material  for  examination  of  tubercle 
bacilli  can  be  produced.  Sticker  {Zentralh.  f.  hi.  Med.,  1891, 
No.  3)  has  recommended  the  use  of  0"2  gr.  of  iodide  of 
potassium,  in  order  to  bring  about  a  catarrh  artificially. 
A.  Frankel  has  not  found  that  this  process  is  productive  of 
special  results.  Kronig  believes  this  method  to  be  not  without 
danger,  and  effects  an  accumulation  of  secretion  during  the 
night  by  means  of  doses  of  morphine,  applying  auscultation 
early  next  morning.  In  this  way  he  often  obtains  sputum 
containing  bacilli. 

Michaelides  and  Much  have  communicated  in  Brauer's 
Beitrdge,  1907,  vol.  8,  Nos.  1  and  2,  that  a  coloured  variety 
of  the  tubercle  bacillus  may  sometimes  be  found  which,  how- 
ever, can  only  be  detected  by  means  of  a  modified  Gram 
staining.  This  species  of  tubercle  bacillus  differs  only  in 
colour,  but  is  otherwise  absolutely  analogous  with  the  typical 
tubercle  bacillus,  in  its  cultured  properties  as  well  as  in 
animal  experiments.  According  to  the  proofs  put  forward^ 
the  occurrence  of  a  species  of  tubercle  bacilli  with  totally 
different  staining  properties  must  be  regarded  as  demonstrated. 
In  fact,  Much  has  succeeded  in  showing  that  the  one  species 
may  sometimes  go  over  into  the  other  {Bed.  klin.  Wueliemichr., 


158  THE  OPHTHALMIC  AND  CUTANEOUS 

1908,  No.  14).  We  must  therefore  include  it  here,  although  it 
cannot  be  denied  that  this  discovery  will  cause  a  good  deal 
of  confusion  in  the  investigation  of  tuberculosis. 

We  should  not  forget  to  mention  the  earlier  studies  of 
Spengler  {Deutsche  med.  IVochenschr.,  1907)  who  also  describes 
various  species  with  very  little  acid-resisting  capacity,  as  also 
some  very  interesting  staining  methods. 

Processes  of  Increase. — Now  we  come  to  the  processes  of 
increase.  This  name  in  reality  belongs  only  to  those  pro- 
cesses in  which  an  increase  actually  takes  place  in  a  nutritive 
medium  by  the  multiplication  of  some  of  the  bacilli,  such  as, 
for  instance,  is  the  case  when  using  the  nutritive  substance 
of  Heyden.  But  as  a  rule  this  designation  is  applied  in  a 
broader  sense,  and  is  used  for  all  attempts  to  demonstrate 
the  presence  of  the  tubercle  bacilli  by  centrifugalizing,  &c., 
the  sputum.  Very  much,  however,  cannot  be  attained  from 
a  practical  point  of  view  with  these  very  carefully  thought- 
out  methods,  and  this  is  the  reason  that  they  are  not  employed 
in  practice  to  any  great  extent.  The  oldest  method  is  con- 
nected with  the  name  of  Biedert  {Berl.  Min.  Wochenschr., 
1886,  Nos.  42,  43).  The  modification  of  Kronig  seems  to  be 
the  best ;  for  dissolving  the  phlegm  he  uses  an  amount  of  O'l 
per  cent,  solution  of  caustic  soda,  six  to  twelve  times  as  great 
as  the  amount  of  sputum,  both  being  thoroughly  shaken  in  an 
Erlmeyer  bulb,  and  heated  during  the  process  of  shaking. 
The  grosser  and  as  yet  undissolved  sputum  particles,  which  do 
not  contain  any  tubercle  bacilli,  are  thrown  out  by  shght 
centrifugalization,  the  remaining  fluid  being  centrifugalized 
together  with  the  tubercle  bacilh  and  the  other  bacteria  for 
some  time,  until  they  are  discovered  in  the  sediment. 

The  method  of  inoscopy  of  Jousset  (see  Exudations)  may 
be  used  in  a  similar  manner  in  the  case  of  sputum. 

Animal  Experiments. — In  all  cases  in  which  the  presence 
of  tubercle  bacilli  cannot  easily  be  ascertained,  the  only 
method  which  cannot  fail  is  to  experiment  on  guinea-pigs. 
By  repeatedly  washing  the  sputum,  in  a  way  similar  to  the 
one  pursued  in  forming  an  influenza  culture,  one  endeavours 
to  wash  away  the  other  bacteria,  so  as  to  prevent  the  animal 
from  dying  prematurely  of  sepsis.  The  method  recently 
recommended  by  Bloch  {Berl.  hlin.  Wochenschr.,  1907,  No.  17), 
of  crushing  the  regional  lymph  gland,  has  provided  myself 
and  others  with  favourable  results,  so  that  it  is  no  longer 
necessary    to    wait    six  or  eight  weeks  for  the  result  of  the 


DIAGNOSIS    OF   TUBERCULOSIS  159 

experiment,  but  so  early  as  after  a  fortnight  it  is  possible  to 
give  a  definite  conclusion  by  extirpating  the  regional  glands 
and  examining  them  for  tubercle  bacilli.  This  decrease  in 
the  time  which  must  elapse  before  the  diagnosis  can  be  pro- 
nounced with  certainty  would  naturally  enhance  the  im- 
portance of  the  animal  experiment.  Other  writers  on  the 
subject  obtained  results  which  were  equally  favourable  (see 
Joannovics  and  Kapsammer,  Berl.  klin.  Wocheiischr.,  1007, 
No.  45  ;  Weber,  Med.  Ges.  in  Giessen,  ref.,  Deutsche  med. 
Wochenschr.,  1907,  No.  47,  p.  1976). 

We  must  also  refer  to  the  method  of  Marmoreck,  who 
observed  that  the  injection  of  tuberculin  a  short  time  after 
the  injection  of  tuberculous  material  caused  a  considerable 
increase  in  the  temperature  ot  the  individual  concerned  (see 
the  Theoretical  Part). 

Lymphocyte  Sputa,  and  their  Significance  for  Early  Dia- 
gnosis.— Recently  I  have  called  attention  (Verein  fiir  innere 
Med.,  November  4,  1907)  to  a  thus  far  unknown  and  very 
peculiar  sputum  discovery,  viz.,  the  occurrence  of  Ij^mphocyte 
sputa,  and  their  significance  for  the  early  diagnosis  of  tuber- 
culosis. The  discovery  has  been  all  the  more  remarkable 
by  reason  of  the  fact  that  it  was  so  very  obvious,  and  E.  Klebs 
confessed  he  had  never  paid  attention  to  the  fact,  but  it  came 
upon  him  with  a  flash,  and  he  believes  that  I  was  right. 
Also  Fritz  Koch  (in  his  referendum  in  the  Milnch.  med. 
Wochenschr.),  who  has  been  assistant  for  a  good  many  years 
in  the  clinic  for  pulmonary  diseases,  and  as  such  has  had 
sufficient  opportunity  to  observe  sputum,  declared  that  the 
sputa  demonstrated  by  me  were  those  which  he  had  always 
suspected  of  containing  tubercle  bacilli,  although  he  and  his 
colleagues  did  not  know  on  what  basis  to  explain  this  instinc- 
tive view.  The  fact  of  the  matter  is  that  lymphocytes  occur 
in  very  large  numbers  in  commencing  and  still  also  in  advanced 
tuberculosis.  The  lymphocytes  sometimes  constitute  as  much 
as  33  to  90  per  cent,  of  the  sputum  cells.  x\nd  if  the  epithelial 
cells — which  arrive  in  the  sputum  by  desquaniation,  and  are 
indicative  of  quite  different  things — are  regarded  as  leucocytes 
and  lymphocytes  migrating  from  the  vascular  passage,  the 
percentage  of  lymphocytes  becomes  much  larger  still.  This 
observation  and  the  frequency  of  its  occurrence  are  very  remark- 
able, especially  if  one  takes  into  account  the  extent  to  which 
the  sputum  from  the  tubercular  centre  is  mixed  with  the  secre- 
tions from  the  nose  and  throat,  and  with  those  from  the  merely 
catarrhal  and  non-tuberculous  parts  of  the  lungs. 


160  THE  OPHTHALMIC  AND  CUTANEOUS 

Now  these  lymphocyte  sputa  are  found  in  cases  clinically 
suspected  of  incipient  tuberculosis  without  tubercle  bacilli, 
in  cases  with  few  tubercle  bacilli,  and  frequently  in  those 
with  numerous  tubercle  bacilli.  These  last-mentioned  cases 
to  some  extent  prove  an  existing  connection  between  the 
lymphocytes  and  the  tubercle  bacilli.  After  this  connection 
has  been  proved  to  exist  their  presence  becomes  of  importance, 
even  in  such  cases  in  which  tubercle  bacilli  have  not  yet  been 
found,  thus  apparentl}^  representing  an  early  symptom  of 
tuberculosis.  I  regard  the  presence  of  lymphocytes  as  a  direct 
indication  of  tubercle  bacilli,  bound  to  appear  in  the  sputum 
at  a  more  advanced  stage  of  the  disease,  in  a  manner  similar 
to  that  of  the  geologist,  who  concludes  that  certain  substances 
must  exist  where  particular  formations  are  found.  Indeed, 
I  have  succeeded  in  finding  one  or  two  tubercle  bacilli  in 
lymphocyte  sputa  after  a  very  long  search,  which  I  was 
induced  to  undertake  by  the  lymphocyte  character  of  the 
sputum. 

It  is  remarkable  also  that  in  so  many  advanced  cases 
lymphocytes  are  found  in  so  high  a  percentage,  especially  if 
one  considers  that  in  advanced  cases  we  have  to  do,  as  a  rule, 
with  mixed  infection,  and  that  the  bacteria  of  the  mixed 
infection  produce  substances  which  have  a  positive  chemo- 
tactic  action  on  the  leucocytes,  and  not,  like  the  toxins  of  the 
tubercle  bacilli,  on  the  lymphocytes. 

In  a  discussion  at  a  meeting  of  the  Verein  fiir  innere  Medi- 
zin,  Arnheim  mentioned  an  observation  he  had  made  in  the 
case  of  whooping  cough,  in  which  he  had  found  lymphocytosis 
— after  a  beginning  of  leucocytosis — in  the  sputum  as  well  as 
m  the  blood,  after  employing  Pappenheim's  pyronin-methyl- 
green  stain.  My  reply  was  to  the  effect  that,  in  using  Pappen- 
heim's stain,  the  epithelial  cells — -w^iich  in  the  advanced  stages 
of  whooping  cough  are  desquamated  in  large  numbers — might 
easily  be  taken  for  lymphocytes,^  and  that  especially  in  the 
sputum,  which  contains  a  great  many  degenerated  cells,  the 
same  difficulties  are  encountered  for  distinguishing  lympho- 
cytes from  swollen  or  degenerated  polynuclear  leucocytes  as 
in  the  exudations.-     In  correction  of   his  statement  he    adds 


'  A.  Wolff,  "Lyinphoidzellenleukamie,"  Zeitsclir.  f.  Miii.  Med.,  vol.  45, 
Nos.  5,  6. 

-  A.  Wolff,  "  Unters.  iiber  Pleuraergiisse,"  Berl,  Min.  II  ocJiefscJir.,  1901, 
Nos.  34,  45  ;  1902,  No.  6. 


DIAGNOSIS    OF   TUBERCULOSIS  161 

that  L.  INIicliaclis  accounts  for  the  appearance  of  lyiuphocytes 
in  the  sputum  by  the  irritation  of  the  lymphatic  apparatus  in 
chronic  infectious  diseases,  the  reply  to  which  is  that  Michaelis 
is  in  concord  with  myself,  and  has  only  called  attention  to  the 
fact  that  in  chronic  inflammations  an  accumulation  of  lym- 
phocytes is  found  in  exudations,  due  to  an  emigration  of 
lymphocytes. 

Chrome  catarrhs  which  have  not  a  bacterial  cause  probably 
occur  very  rarely  in  the  lungs,  and  it  is  on  account  of  this  fact 
that  the  presence  of  lymphocytes  in  the  sputum  is  of  so  great 
an  importance  as  an  early  symptom  of  tuberculosis.  Whether 
a  chronic  bronchitis  of  a  non-bacterial  character  can  produce 
a  lymphocyte  sputum  (L.  Michaelis,  "  Discussions,"  Verein 
f.  innere  Med.,  November  4,  1907)  is  a  problem  for  later 
investigation,  the  solution  of  which  will  be  considerably  aided 
by  the  new  diagnostic  local  tuberculin  reaction  in  discovering 
whether  or  not  the  presence  of  lymphocytes  in  the  sputum 
in  cases  of  chronic  catarrh  points  to  a  tubercular  etiology. 

For  relations  existing  between  the  tubercle  bacilli  toxins 
and  the  emigration  of  lymphocytes  and  their  role  as  lym- 
phocyte producers  I  refer  to  the  chapters  on  these  subjects. 

The  Pathological  and  Diagnostic  Significance  of  the  Pre- 
sence of  Lymphocytes. — I  will  only  mention  here  that  in  my 
opinion  the  emigration  of  lymphocytes  is  not  only  a  character- 
istic of  the  toxins  of  the  tubercle  bacilli ;  there  is  no  doubt 
that  it  may  also  be  caused  by  other  processes.  I  have 
frequently  adduced  the  investigations  of  Senator  {Virchoto's 
Archiv,  vol.  181)  (see  Schniitgen,  Berl.  Idin.  Wochenschr., 
1907,  No.  45),  according  to  which  lymphocytes  are  found  in 
the  sediment  in  chronic  nephritis ;  I  also  refer  to  the  discovery 
of  lymphocytes  in  the  lumbar  fluid  in  tabes  and  syphihs,  and 
to  the  discovery  published  by  Torday  and  myself  of  lym- 
phocyte exudations,  not  only  after  peritoneal  tuberculin  injec- 
tions, but  also  after  the  injection  of  tetanus  toxin,  and  to  a 
few  other  communications.  Here  I  am  dealing  with  the 
undeniable  discovery  of  lymphocytes  in  the  walls  of  arteries, 
which  I  obtained  after  cerebral  injections  of  tuberculin  and 
endotoxins.  But  even  if  Arnheim  were  right  in  maintaining 
that  lymphocyte  sputa  occur  in  whooping  cough,  this  would 
not   in   the   least    impair   the   diagnostic    significance   of   the 


1  A.  Wolff  and  v.  Torday,  Exper.  Erzeugung  von  Lyniphozytenexsudaten 
Berl.  Min.  WochcnscJir.:' 'l90i.  No.  49. 

11 


162  THE  OPHTHALMIC  AND  CUTANEOUS 

discovery,  because  clinically  it  does  if  whooping  cough  and 
tuberculosis  are  interchanged  ;  besides,  accumulations  of 
lymphocytes  are  of  so  rare  an  occurrence  that  differential 
diagnostic  conclusions  may  be  drawn :  that  is  to  say,  the 
presence  of  all  ordinary  bacteria  and  causes  of  inflammation 
may  be  excluded.  Since  it  is  just  in  the  sputum  that  we 
need  not  take  into  consideration  any  confusion  between  the 
lymphocyte  producers  known  so  far  (tetanus  toxin,  syphilis, 
tabes),  I  am  of  opinion  that  the  presence  of  lymphocyte  sputum 
is  of  very  great  significance  for  the  early  diagnosis  of  pul- 
monary tuberculosis,  and  for  this  reason  I  take  the  oppor- 
tunity of  calling  attention  to  this  fact  (see  reproductions  in 
tables  1  and  2). 

Technically  speaking,  no  difficulties  are  attached  to  the 
demonstration  of  the  presence  of  lymphocyte  sputa  apart  from 
the  morphological  differential  diagnosis.  The  lymphocytes 
can  easily  be  recognized  by  means  of  the  preparation  stained 
by  Loffler's  methylene  blue ;  as  a  rule  the  simple  method  of 
double  staining  with  methylene  blue  suffices.  It  is  only 
necessary  to  consider  the  possibility  of  the  presence  of  lym- 
phocytes, and  not  merely,  in  the  examination,  to  rely  on  the 
presence  of  red  rods. 

The  Examination  for  Elastic  Fibres. — This  process  used  to 
be  the  only  one  by  which  a  diagnosis  could  be  formed  from 
the  sputum  with  regard  to  an  ulcerating  puhnonary  phthisis. 
At  the  present  day  the  presence  of  elastic  fibres  is  still  of  great 
significance,  enabling  us  to  form  a  picture  of  the  destruction 
of  the  pulmonary  tissue.  The  process  has  passed  into  oblivion 
undeservedly,  partly  by  reason  of  the  fact  that  nowadays  the 
examination  of  stained  objects  is  preferred. 

I  warmly  recommend  the  modified  method  of  L.  Michaelis 
for  the  examination  of  elastic  fibres  {Ver.  f.  innere  Med., 
1901),  which  enables  us  to  definitely  ascertain  the  presence  of 
even  the  most  minute  particles  of  elastic  fibre.  Considering 
the  great  significance  of  the  results  obtained  by  this  very 
simple  method,  it  is  far  too  little  employed. 

The  sputum  is  spread  out  in  the  ordinary  way  on  the 
slides  (not  too  thin  a  layer).  The  slides,  which  should  be  dry, 
but  otherwise  unfixed,  are  put  for  a  quarter  of  an  hour  into 
Weigert's  solution  for  elastic  fibres.  After  staining  apply  a 
short  differentiation  with  a  1  per  cent,  hydrochloric  acid 
alcohol  solution.  The  preparations  are  dried,  and  the  whole 
of  the  slide  is  given  a  thin  cover  of  cedar  oil,  so  as  to  avoid 


DIAGNOSIS   OF   TUBERCULOSIS  163 

using  four  cover-glasses;  then  the  preparation  is  thoroughly 
examined  at  suspected  spots  by  means  of  objective  No.  >]. 

The  elastic    tibres   present    a  beautiful  steel-blue   colour  ; 
they  cannot  possibly  be  confused  with  other  formations. 


THERMOMETRY. 

I  will  not  dwell  long  on  the  subject  of  thermometry,  bi,it 
in  a  work  on  the  early  diagnosis  of  tuberculosis  thermometry 
may  not  be  omitted.  It  is  almost  certain  that  a  tuberculous- 
infected  organism  shows  a  special  change  of  temperature,  and 
an  increase  in  the  temperature  may  occur  with  very  little 
cause.  Although  such  increases  most  frequently  occur  at 
night,  yet  they  are  not  limited  to  any  particular  time,  and  for 
this  reason  in  such  cases  the  temperature  should  be  taken 
every  two  hours  (compare  Turban,  Hess,  Cornet,  Penzoldt, 
Hochstetter,  Biirgelin,  Kronig). 

Although  in  other  respects  everything  is  done  for  the 
patients  in  Germany,  one  objects  to  taking  the  temperature 
every  two  hours.  One  dare  not  entrust  this  to  the  already 
over-worked  assistants.  As  a  matter  of  fact  the  additional 
work  would  not  be  so  very  much,  especially  in  view  of  the  fact 
that  the  diagnosis  based  on  it  is  of  so  very  great  importance. 
The  cause  for  this  objection  lies  chiefly  in  the  technical  difd- 
culties  encountered  in  the  use  of  the  thermometers  employed 
in  Germany,  which  require  ten  or  more  minutes  for  exact 
measurement,  notwithstanding  the  fact  that  they  are  sold  as 
"  minute  thermometers " ;  they  are  a  torment  to  doctors, 
nurses,  and  patients  alike. 

Advantages  of  the  Americ(i)i  Thermometer. — I  have  con- 
vinced myself  of  the  fact  that  the  American  thermometers 
possess  great  advantages  over  those  used  in  Germany,  and 
that  they  actually  allow  of  taking  a  certain  and  reliable 
measurement  in  one  minute.  This  is  due  to  the  fact  that  in 
American  thermometers  of  good  manufacture  the  amount  of 
mercury  present  in  the  reservoir  is  very  small,  and  it  takes 
very  little  time  to  become  warm.  Since  the  tube  has  very 
minute  dimensions  in  consequence,  the  temperature  is  not 
read  directly  from  it,  but  is  viewed  through  a  prism  which 
enlarges  the  appearance  of  the  mercury.  The  prism  is  con- 
tained in  the  thermometer  itself,  its  anterior  surface  being  cut 
prismatically.  At  first  it  is  somewhat  difficult  to  read  these 
thermometers,   but  tliese  (lilficulties  are  soon  overcome,  even 


164  THE  OPHTHALMIC  AND  CUTANEOUS 

by  laymen,  and  then  it  becomes  more  easy  to  read  the 
American  thermometers  than  the  German  one.  It  is  also 
much  easier  to  shake  them  down. 

Where  to  take  the  Temperature. — The  anus  is  the  place 
most  appropriate  for  takin<?  the  temperature,  providing  the 
roost  reliable  results.  The  measurements  obtained  in  the 
armpit  are  most  unreliable,  and  may  easily  be  wrong  altogether 
if  the  armpit  has  been  rubbed  beforehand.  In  cases  in  which 
small  differences  in  the  temperature  form  the  basis  of  impor- 
tant conclusions,  the  measurement  should  never  take  place  at 
the  armpit.  The  mouth  measurement  is  reliable  except  in 
cases  in  which  the  patient  has  acquired  the  habit  of  breathing 
through  the  mouth,  or  when  the  patient  has  been  a  long  time 
in  the  open  in  cool  weather. 

The  change  in  the  regulation  of  the  temperature  in  cases 
of  early  tuberculosis  is  especially  evident  from  increases  in 
the  temperature  after  slight  bodily  exertion,  such  as  a  walk. 
For  this  reason  the  dentations  in  the  temperature  curves 
caused  by  such  exertions  support  the  other  diagnostic  con- 
clusions to  a  considerable  extent.  (Penzoldt,  Mi'inch.  med. 
Wochenschr.,  1899,  Ko.  15,  1903,  No.  1;  Meissen,  Thera^j. 
Monatsh.,  November,  1898.) 

On  the  other  hand,  one  must  consider,  with  A.  Frankel 
(p.  717),  that  convalescent  patients  may  show  a  similar  change 
in  the  temperature  after  acute  chlorotic  and  other  diseases. 

In  guinea-pigs  there  is  also  a  change  in  the  temperature 
after  tuberculin  injections,  manifesting  itself  as  apparently 
irregular  rises  and  decreases  in  the  temperature,  even  in 
injecting  the  same  dose  in  different  animals  or  repeating  the 
injection  in  the  same  animal.  I  mention  these  facts  chiefly 
because  these  temperature  changes  can  only  be  found  out  if 
the  temperature  is  taken  very  frequently ;  sometimes  they 
have  ceased  so  early  as  an  hour  after  the  injection. 

The  rises  in  the  temperature  after  tuberculin  injections  in 
man  are  due  within  six  hours  in  a  typical  reaction.  In  our 
tuberculin  injections  (see  tables  3  and  4)  a  very  considerable 
rise  in  the  temperature  sometimes  did  not  occur  till  after 
twenty-four  or  more  hours  had  passed  since  the  injection. 
I  believe  this  to  have  been  due  to  the  fact  that  we  had  not 
to  do  with  active  but  with  more  or  less  latent  tuber- 
cular centres,  since  probably  it  is  only  in  the  case  of  fully 
active  centres  that  a  direct  reaction  takes  place  (see  the 
Theoretical  Part). 


DIAGNOSIS    OF   TUBERCULOSIS  165 

THE    RONTGEN    METHOD    AND    ITS   APPLICATION   FOR   THE 
DIAGNOSIS   OF   TUBERCULOSIS, 

Especially  for  the  Earlij  Diagnosis  of  Pulmonary  Tuberculosis. 

It  could  not  but  be  expected  that  the  Kontgen  method, 
which  had  been  successfully  applied  in  so  many  departments 
of  medicine,  should  be  made  use  of  in  internal  medicine, 
especially  for  the  early  diagnosis  of  pulmonary  tuberculosis. 
The  results  obtained  by  the  Eontgen  method  in  internal 
medicine  naturally  have  not  been  so  pronounced  as  those 
obtained  in  surgery,  and  the  examination  by  a  thoroughly 
experienced  clinician  is  more  to  be  depended  upon  as  a  rule 
than  a  Rontgen  photography.  Thus  it  came  about  that  for 
a  long  time  the  Rontgen  method  was  only  used  for  confirming 
the  internal  diagnosis,  especially  of  mediastinal  tamours  and 
aorta-aneurysms ;  also  for  didactic  purposes  in  academic  in- 
struction, for  demonstrating  the  correctness  of  the  conclusions 
arrived  at  by  clinical  examination. 

It  has  only  been  different  since  the  new  orthodiagraphic 
method  has  made  it  possible  to  combine  quantitative  measure- 
ments with  the  Rontgen  method.  Thus  we  have  obtained 
one  of  the  few  clinical  methods  which  enable  us  to  give  exact 
measurements,  and  as  such  it  is  undoubtedly  of  great  clinical 
value.  However,  the  refinement  of  the  method  has  increased 
the  cost  of  the  apparatus  and  the  difficulties  of  investigation 
to  such  an  extent  that  it  is  absolutely  impossible  to  employ 
this  method  in  all  clinical  examinations,  whilst  at  the  same 
time  the  technique  of  this  procedure  has  become  a  speciality 
which  can  only  very  rarely  be  combined  with  clinical  procedure, 
namely  in  such  cases  in  which  the  cUnician  in  question  does 
not  wish  to  employ  any  methods  of  experimental  confirmation. 

Cost  and  trouble,  time,  and  many  other  things  would  be 
no  object  if  only  the  Rontgen  method  could  reveal  to  us 
important  scientific  truths,  or  were  of  benefit  in  individual 
cases.  In  recent  times  a  whole  literature  has  been  created 
on  the  subject,  chiefly  dealing  with  the  refined  Rontgen  method 
as  employed  for  the  diagnosis  of  tuberculosis  of  the  bronchial 
glands,  and  for  the  early  diagnosis  of  pulmonary  tuberculosis. 
For  this  reason  we  will  very  briefly  investigate  the  basis 
which  underlies  the  application  of  the  Rontgen  rays  for  the 
early  diagnosis  of  tuberculosis. 

The  Volume  of  the  Lungs.— The  enormous  change  in  the 
volume    of   the    lungs   by  deep  breathing   can   be   very    well 


166 


THE  OPHTHALMIC  AND  CUTANEOUS 


seen  by  means  of  the  Eontgen  reflector,  and  better  still  bj' 
orthodiagraphy  according  to  Moritz.  We  here  reproduce  an 
orthodiagraphic  picture  according  to  Francke,  showing  most 
precisely  the  expansion  in  a  healthy  lung.  It  is  quite  possible 
to  obtain  an  idea  of  the  expansion  capacity  of  the  lungs, 
with  exception  of  the  apices  (for  even  by  means  of  Kronig's 
apical  percussion  it  is  impossible  to  observe  a  direct  superior 
extension  of  the  apex  such  as  is  shown  in  this  drawing),  by 


Pig.  3. — Sketch  of  the  extension  of  the  lungs  as  indicated  by  the  ortho- 
diagraphic method  (according  to  Francke).  I,  in  expiration  ;  II,  during  the 
breathing  pause  ;  III,  in  a  very  strong  inspiration. 


means  of  percussion.  But  every  clinician  who  has  endeavoured 
to  form  a  mental  picture  of  the  extension  of  the  lung  in 
breathing  on  the  basis  of  percussion  observations  will  be 
surprised  to  find  that  by  means  of  the  orthodiagraphic  method 
il.  has  been  found  that  the  surfaces  of  the  anterior  portions 
of  both  lungs  (see  above,  fig.  3)  increase  from  134  to  254 
square  cm.  :  that  is  to  say,  about  80  per  cent.  Special 
measurements  have  shown  that  the  apices  rise  to  about 
1*3  cm.  higher  than  they  are  during  the  breathing  pause 
and  after  the  very  deepest  expiration.  The  inner  lower 
width   of  the  thorax  onl}'  increases   from  22'15  to  25*6,  the 


DIAGNOSIS    OF   TUBERCULOSIS  1()7 

height  of  the  kings,  on  the  other  hand,  from  12-02  to  18-52. 
The  hmg  surfaces  drop  from  254  to  144  (about  31  per  cent.) 
from  the  deepest  inspiration  to  the  breathing  pause,  and  from 
the  latter  to  the  deepest  expiration  to  138 — that  is,  only  14 
per  cent,  less  than  the  original  expanse. 

These  measurements,  taken  in  a  healthy  boy  aged  15,  may 
represent  a  specially  strong  expansion  of  the  lungs,  and  by 
reason  of  the  age  and  other  physiological  conditions  of  the 
subject,  which  could  not  be  regarded  as  being  strictly  patho- 
logical, the  lungs  could  easily  have  moved.  However,  these 
observations  and  a  number  of  analogous  ones  suffice  to  show 
that  the  healthy  lung  acts  very  regularly  and  deeply,  and  that 
especially  the  apices  and  the  bases  play  a  very  important  part 
in  the  act  of  breathing.  These  conditions  have  lately  been  very 
much  taken  into  account  by  clinicians,  especially  by  Kronig, 
as  being  of  importance  in  forming  a  diagnosis  ;  it  is  probable 
that  they  have  been  induced  to  do  so  in  consideration  of  the 
results  obtained  by  the  Eontgen  method.  And  although  it  is 
possible  (as  we  shall  see  a  little  further  on)  to  arrive  at  the 
breathing  conditions  of  the  lung  by  means  of  a  perfected 
method  of  percussion,  yet  the  very  refined  Eontgen  diagnosis 
has  the  advantage  of  enabling  us  to  express  the  breathing  con- 
ditions of  the  lungs  numerically,  thus  preventing  a  tiresome 
discussion  which  arises  with  each  discovery  through  percus- 
sion, for  the  simple  reason  that,  notwithstanding  Oestreich's 
example,  even  to-day  percussion  is  never  performed  jjo.s^  mortem, 
the  precise  verification  oi  post-mortem  discoveries  by  percussion 
being  still  connected  with  great  difficulties,  and  sometimes 
may  require  frozen  section,  &c. 

Even  m  quite  initial  lung  processes  the  type  of  breathing 
at  the  apex  changes  as  well  as  the  one  at  the  base,  and  for 
this  reason  I  regard  the  observing  and  determining"  of  the 
quantitative  breathing  conditions  as  very  important  measures 
for  the  support  of  the  purely  clinical  diagnosis ;  it  is  not  of 
greater  value  than  the  latter,  but  controls  and  supplements  it. 
The  same  may  be  said  concerning  the  Eontgen  method  for 
determining  the  initial  stages  of  pulmonary  tuberculosis  ; 
I  am  not  referring  to  tuberculosis  of  the  bronchial  glands, 
which  it  is  very  difficult  to  determine  clinically,  and  which 
it  is  much  easier  and  more  certain  to  determine  by  means  of 
the  Eontgen  investigation.  We  shall  deal  more  extensively 
with  its  diagnosis  a  little  further  on. 

The  diagnosis    of  pulmonary  processes    by  means   of   the 


168  THE  OPHTHALMIC  AND  CUTANEOUS 

Eontgen  method  must  necessarily  be  based  on  the  fact  that 
the  diseased  parts  exhibit  a  kind  of  transparency  to  the  Rontgen 
rays  different  from  the  healthy  ones.  To  put  it  briefly,  we 
look  for  dark  spots  on  the  screen  on  which  the  patient's 
shadow  is  thrown.  Now,  if  we  endeavour  to  make  a  mental 
picture  of  the  pathologico-anatomical  processes  chiefly  con- 
cerned in  tuberculous  processes,  we  shall  find  that  we  have 
to  do  principally  with  inflammatory  exudative  and  infiltra- 
tive changes  leading  to  shrinkage.  Authors  are  fairly  unani- 
mous in  maintaining  that  the  exudative  forms  can  hardly  be 
recognized  by  means  of  the  Rontgen  method,  so  that  only 
the  infiltrative  forms  remain,  and  of  these  latter  only  those 
infiltrative  processes^  are  clearly  defined  which  in  their  course 
have  formed  retractions,  shrinking,  and  scars.  This  is  due 
partly  to  the  fact  that  the  tissue  of  scars  is  more  opaque  to 
rays,  partly  and  chiefly  to  the  accumulation  of  coal  pigment 
in  these  scars.  Now  it  cannot  be  doubted  that  the  infiltrative 
and  especially  the  retractive  forms  present  comparatively  but 
little  difficulty  to  the  clinical  diagnosis  of  pulmonary  tuber- 
culosis, whilst  they  really  only  exist  in  the  early  stages  of 
the  disease,  in  which  there  is  as  yet  no  trace  of  infiltration  and 
retraction. 

This  does  not  by  any  means  exhaust  the  difficulties  in  the 
way  of  the  Rontgen  method.  It  is  hardly  necessary  for  me 
to  dwell  on  the  fact  that  the  flickering  shadow  on  the  screen, 
even  when  contracted  by  means  of  the  orthodiagraphical 
method,  merely  provides  us  with  a  purely  subjective  method, 
not  by  any  means  better  than  percussion.  The  formation  of 
the  thorax  causes  the  shadow  to  be  of  different  intensity  at 
various  parts  of  the  lung  surface,  whilst  the  ribs  also  throw 
very  distinct  shadows  on  to  the  screen.  But  even  apart  from 
this  the  surface  of  the  lung  would  not  be  homogeneous  ;  it 
leaves  a  shadow  for  the  root  of  the  lung,  one  for  the  breast, 
and  in  stout  people  one  for  the  complementary  space  in  the 
pleura ;  to  this  three  more  shadows  are  to  be  added,  caused 

^  "  The  very  early  beginnings,  tubercle  nodules  or  diffuse  gelatinous 
infiltrations,  cannot  be  demonstrated  by  the  Eontgen  process."  The 
author  (Eieder)  adds  :  "  Just  as  little  as  by  the  other  clinical  methods  of 
investigation.  Tubercular  centres  of  somewhat  greater  extension  cannot, 
however,  be  missed  by  a  thorough  Rontgen  investigation."  Fresh,  pro- 
gressive centres  show  weakly  outlined  and  diffused  shadows,  whilst  older 
centres  of  infiltration,  with  shrinking  and  calcification,  give  very  dark 
shadows  with  better  outlines. 


DIAGNOSIS   OF   TUBERCULOSIS 


109 


by  the  bending  of  the  thoracic  wall,  since  towards  the  border 
the  rays  have  to  penetrate  through  layers  of  increasing 
thickness. 

I  here  reproduce  the  schematic  picture  according  to 
Francke,  which  shows  these  conditions  very  clearly.  The 
upper  part  of  the  shadow  caused  by  the  bending  coincides 
with  the  region  of  the  apex,  which  really  is  the  most  impor- 
tant, whilst  at  the  same  time  in  this  region  are  found  the 
scapula  and  the  muscles  of  the  arm  and  shoulder.  The 
muscles  surrounding  the  apices,  especially  at  the  back,  cause 
a  darker  shadow  in  this  region  even  in  healthy  individuals, 
also  in  those  parts  of  the  apices  in  which  the  shadows  of 
the  ribs  and  the  clavicle  do  not  appear. 


Fig.  4.— Scheme  according  to  Fraucke  (loc.  cit.).  a,  Shadow  of  the  root  of 
the  lung;  /;,  upper  shadowy  region;  c,  system  of  the  mammary  glands  in 
females  ;  d,  shadow  in  stout  individuals. 


Then  we  have  still  to  consider  that  in  this  fairly  dark 
region  surrounded  by  bones  we  often  find  very  small  differ- 
ences in  the  shadow  caused  by  differences  in  the  development 
of  the  muscular  system,  and  this  again  is  connected  with  a 
different  development  of  the  bones.  Furthermore,  we  must 
consider  the  frequently  occurring  one-sided  scoliosis,  and  the 
difference  in  the  situation  of  the  bones  in  the  upper  thorax 
aperture,  by  which  it  is  accompanied.  The  first  two  ribs  are 
frequently  situated  close  together,  and  in  that  case  do  not 
allow  many  sagittaliy  directed  Rontgen  rays  to  pass,  whilst 


170  THE  OPHTHALMIC  AND  CUTANEOUS 

ribs  that  are  far  apart  give  the  apex  an  appearance  which 
is  even  lighter  than  that  which  would  correspond  to  the 
condition  of  the  soft  parts.  Thin  and  narrow  first  ribs  give 
the  impression  of  a  high  position  of  the  lungs,  whilst  thick 
and  broad  ribs  give  the  impression  of  depression  of  the  lungs. 

To  put  it  concisely,  in  healthy  individuals  also,  one 
observes,  as  a  rule,  a  difference  in  the  expansion  of  the  lungs 
in  both  sides.  The  Kontgen  method  does  not  give  reliable 
information  as  to  the  condition  of  the  apices,  the  lightness  in 
the  region  of  the  apices  being  different  both  right  and  left, 
even  in  healthy  individuals  (compare  the  tables  of  the  atlas  by 
Ziemssen-Eieder  ;  also  see  Kieder,  "  Zur  Diagnose  der  chroni- 
schen  Lungen-tuberkulose  durch  das  radiologische  Verfahren,"" 
Fortschritte  auf  clem  Gehiete  der  Bdntgenstrahlen,  vii.,  p.  1  ; 
Holzknecht,  "  Die  rontgenologische  Diagnostik  der  Erkran- 
kungen  der  Brusteingeweide,"  Hamburg,  1901 ;  Weinberger, 
"  Atlas  der  Eadiographie  der  Brustorgane,"  Vienna,  1901 ;  and 
Grashey,  "  Atlas  typischer  Kontgenbilder  vom  normalen  Men- 
schen,"  Munich,  Lehmann,  1905,  plate  20). 

For  the  orthodiagraphical  examination  a  vertical  ortho- 
graph  is  required.  The  subject  to  be  examined  must  breathe 
slowly  and  very  deeply  ;  he  must  move  his  arms  alternately 
to  the  front  and  the  back,  so  as  to  remove  as  much  as  possible 
the  harness  of  bones  from  the  apices.  For  the  same  purpose 
the  tube  has  to  be  moved  to  and  fro,  so  as  to  find  a  favourable 
spot  for  the  rays  to  penetrate,  and  finally  the  body  itself  has 
to  be  moved  to  and  fro  in  front  of  the  tube  in  order  that  the 
latter  may  send  its  rays  alternately  through  the  front  and 
the  back  of  the  body.  Our  explanations  have  shown  that  all 
these  measures  do  not  give  a  result  justifying  the  expenditure 
of  trouble,  time  and  money,  and  that  the  penetration  of 
the  apices  by  these  rays  does  not,  as  a  rule,  give  any 
results  enabling  us  to  form  an  early  diagnosis  of  pulmonary 
tuberculosis. 

This  view  is  not  in  the  least  affected  by  the  fact  that 
Arnsberger  {Miinch.  med.  WochenscJir.,  1907,  No.  2)  has  ob- 
served in  almost  all  cases  changes  in  the  transparency  and 
size  of  the  apical  regions,  differences  in  the  transparency 
in  the  act  of  breathing,  and  more  opacity  in  inspiration. 
Neither  is  it  influenced  by  Pforringer  and  Bunz  (ibid.)  who 
attach  great  value  to  the  Eontgen  investigation,  nor  by  Tier- 
huff's  publication  {Deutsche  med.  Woclienschr.,  1907,  No.  15), 
all  of  whom  claim  to  have  detected  tubercular  centres — which 


DIAGNOSIS    OF   TUBERCULOSIS  171 

could  hardly,  or  not  at  all,  have  heen  found  by  percussion 
and  auscultation — by  means  of  the  Kontgen  method.  Briihl 
remarks  in  the  International  Zentralblatt  filr  die  gesanunte 
TiiberJiuloseforschung,  1907,  p.  23,  and,  I  believe,  rightly, 
that  the  cases  adduced  can  hardly  be  regarded  as  constituting 
proofs  for  the  contentions  of  the  authors. 

Of  the  most  recent  investigations,  those  carried  out  by 
Adam  in  conjunction  with  Albers-Schoneberg  in  the  St. 
Georg  Hospital  in  Hamburg  {Fortschritte  auf  clem  Gehiete 
der  Bontgenstr allien,  vol.  10,  p.  182)  are  the  most  valuable  ; 
in  70  cases  comparisons  have  been  drawn  between  the  most 
thorough  clinical  examinations  and  the  results  obtained  by 
means  of  the  Rontgen  method.  Together  with  the  passing 
of  the  rays  through  the  body,  the  authors  lay  great  stress  on 
Eontgen  photography  by  means  of  compression  diaphragm 
tubes,  the  patient,  lying  on  his  back,  his  breath  drawn  in, 
photographed  ventrodorsal ly  with  soft  tubes.  These  radio- 
graphs are  said  to  be  very  clear,  showing  cloudy  shadows  in 
the  regions  of  the  apices  in  those  cases  in  which  the  ordinary 
penetration  of  the  rays  and  the  physical  investigation  had 
not  given  any  result.  According  to  Adam,  fresh  catarrhal 
affections  of  the  apices  are  not  shown  in  the  Eontgen  picture ; 
but  he  is  of  opinion  that  the  method  can  be  used  in  those 
cases  in  which  the  disease  does  not  show  any  catarrhal 
symptoms,  but  for  a  long  time  takes  the  form  of  a  chronic 
infiltrative  process. 

His  view  is  essentially  in  harmony  with  our  explanations 
as  given  above.  We  will  only  further  add  that  we  are  of 
opinion  that  for  the  infiltrative  forms  we  are  much  less  in 
need  of  a  method  supporting  the  diagnosis  than  of  one  for 
the  catarrhal  forms.  Practically  the  same  conclusions  were 
adopted  at  the  Eontgen  Congress  in  April,  1907,  which  was 
held  directly  after  the  Chirurgical  Congress,  and  which  occu- 
pied itself  chiefly  with  the  early  diagnosis  of  pulmonary  tuber- 
culosis by  means  of  Eontgen  rays. 

THE  DIAGNOSIS  OF  TUBERCULOSIS   OF    THE   BRONCHIAL   GLANDS. 

The  diagnosis  of  tuberculosis  of  the  bronchi  is  very  diffi- 
cult :  that  is  to  say,  as  compared  with  the  diagnosis  of  the 
ordinary  forms  of  lung  tuberculosis.  It  is  known,  however, 
that  tuberculosis  of  the  bronchial  glands  is  a  disease  which 
most  frequently  occurs  in  children,  and  recent  investigations 


172  THE  OPHTHALMIC  AND  CUTANEOUS 

have  shown  that  probably  there  is  a  genetic  connection 
between  tuberculosis  of  the  bronchial  glands  and  tuberculosis 
of  the  apices,  and  for  this  reason  great  interest  is  attached 
to  the  diagnosis  of  the  former.  However  difficult  it  is  to  form 
a  clinical  diagnosis  of  tuberculosis  of  the  bronchial  glands  in 
living  people/  yet  it  must  be  admitted  that  a  diagnosis  is 
not  by  any  means  impossible,  and  if  the  attention  is  directed 
to  the  probability  of  its  existence  it  may  fairly  easily  be 
formed  in  quite  a  number  of  cases. 

We  deal  with  bronchial  tuberculosis  after  having  dealt 
with  the  Eontgen  method,  because  this  method — in  contrast 
with  its  value  for  diagnosing  tuberculosis  of  the  apices — is  of 
greater  importance  in  diagnosing  tuberculosis  of  the  bronchial 
glands. 

We  know  from  the  mediastinal  tumours  and  the  aneurysms 
of  the  ascending  aorta  that  the  anterior  mediastinum — not- 
withstanding the  sternal  plate  in  front  of  it — is  so  accessible 
to  the  Kontgen  rays  that  the  Rontgen  diagnosis,  as  a  rule, 
does  not  meet  with  any  difficulty.  I  have  directed  my  atten- 
tion specially  to  the  tumours  of  the  mediastinum  in  the 
material  at  my  disposal  in  the  Berlin  University  polyclinic 
and  the  University  consultations  for  the  poor,  and  I  have 
found  that  mediastinal  tumours  are  of  comparatively  frequent 
occurrence  and  clinically  can  fairly  easily  be  recognized.  The 
correctness  of  the  clinical  diagnosis  was  controlled  in  each 
case  by  a  Eontgen  photograph  in  the  University  Eontgen 
Institute  (Professor  Grunmach). 

I  mention  here  specially  the  mediastinal  tumours,  because 
these  give  physical  appearances  similar  to  tuberculous  bron- 
chial glands,  due  to  the  fact  that  both  show  the  same  con- 
traction of  space.  The  signs  here  influence  the  veins  opening 
out  in  the  large  reservoir,  they  depress  the  bronchi,  and  may 
even  displace  the  lungs.  As  a  result,  we  get  signs  which 
can  be  seen  physically  and  allow  of  a  comparatively  easy 
diagnosis. 

According  to  Sturtz  (Metz,  Fourth  Congress  of  Tubercu- 
losis Specialists,  May  24  and  25,  1907),  tuberculosis  of  the 
bronchial  glands  is  of  quite  frequent  occurrence  ;  the  swollen 


'  See  A.  Fritnkel,  "  Lungenkrankheiten,"  p.  774 :  "  The  symptoms  of 
tuberculosis  of  the  bronchial  glands  are  uncertain,  and  even  those  that  are 
not  quite  reliable  are  frequently  not  present." 


DIAGNOSIS    OF    TUBERCULOSIS  It'-i 

glands  can  easily  be  seen  in  the  Rontgen  picture' ;  with  them 
streaks  are  observed,  the  shadows  of  cords  going  to  the  lung 
and  especially  to  the  apex.  In  this  manner  tuberculosis  of 
the  bronchial  glands  is  supposed  to  cause  tuberculosis  of  the 
apices.-  In  the  discussion  following,  this  view  was  upheld 
by  M.  Wolff,  on  the  basis  of  Rontgen  pictures,  and  by  Benda, 
on  that  of  pathologico-anatomical  observations,  the  latter, 
at  any  rate,  in  so  far  as  in  children  pulmonary  tuberculosis 
is  more  frequently  the  result  of  tuberculosis  of  the  bronchial 
glands  than  the  opposite  is  the  case,  as  was  maintained  by 
a  few  speakers. 

The  results  obtained  by  one  diagnostic  method — that  of 
the  radiograph — have  already  been  briefly  mentioned.  Now 
it  is  impossible  to  examine  every  child  by  means  of  Rontgen 
rays ;  such  an  investigation  must  have  a  justification,  and  for 
this  reason,  notwithstanding  the  splendid  results  obtained  by 
the  penetration  of  the  Rontgen  rays  and  the  radiograph,  the 
physical  signs  may  not  be  disregarded,  especially  if  they,  by 
themselves,  sufiice  to  form  a  definite  diagnosis.  The  applica- 
tion of  all  methods  at  our  disposal  will  be  especially  justified 
in  those  cases  in  which  the  new  diagnostic  tuberculin  methods 
indicate  the  presence  of  a  tuberculous  centre,  the  site  of  which 
remains  undisclosed  by  the  ordinary  clinical  examination. 

The  signs  of  displacement  mentioned  above  are  due  to  the 
pressure  of  the  bronchial  glands  on  the  venous  centre  and  the 
principal  bronchus.  In  such  cases  also  a  displacement  of  the 
lung  itself  will  occur  through  the  foreign  contents  of  the 
mediastinum.  It  is  due  to  this  similarity  of  action  that 
almost  the  same  symptoms  are  present  in  aneurysm  of  the 
aorta,  in  mediastinal  tumours  of  a  benignant  and  malignant 
nature,  in  pseudo-leucocytha?mic  tumours,  and  in  tuberculosis 
of  the  bronchial  glands. 

The  pressure  of  the  tumour  and  the  swollen  glands  on  the 


'  A.  FrJinkel  (p.  775)  has  shown  that,  according  to  Kelscli,  Bouchard 
and  Claude,  and  Eosenfeld,  enlarged  bronchial  and  mediastinal  glands 
are  to  be  seen  as  round  and  dark  spots  in  the  region  of  the  upper 
thoracic  spine,  especially  on  the  right  side  ;  on  the  left  side  the  shadow- 
thrown  by  the  heart  prevents  observation.  But  Friinkel  at  the  same  time 
calls  attention  to  the  fact  that  outHned  shadows  of  the  lung  parenchyma 
may  present  similar  pictures. 

-  A.  Friinkel  points  out  that  it  is  just  by  reason  of  the  frequency  of 
bronchial  tuberculosis  that  in  the  case  of  children  lung  tuberculosis  fre- 
quently does  not  begin  at  the  apex,  but  rather  in  the  middle  of  the  lung. 


174  THE  OPHTHALMIC  AND  CUTANEOUS 

veins  causes  an  obstruction  in  the  veins  in  this  region,  as  also 
in  those  which  are  not  lying  so  very  deeply,  and  those  that 
have  their  course  in  the  skin,  especially  the  veins  of  the 
mammary  glands.  The  swelling  of  the  veins  in  the  outer 
skin,  especially  of  the  external  thoracic  veins,  constitutes  the 
most  important  and  definite  sign  of  an  obstruction  originating 
in  the  region  of  the  mediastinum. 

This  apparently  so  harmless  sign  should  not  be  taken  too 
lightly  ;  the  influx  in  the  mediastinum  under  normal  conditions 
is  so  favourable,  and  an  obstruction  of  the  efflux  by  breathing, 
&c.,  is  so  out  of  the  question  by  reason  of  the  bony  thorax, 
that  any  visible  obstruction    in   this   part   points   to  a  com- 
pression of  the  veins  originating  in  the  mediastinum.     Sirakoff 
{Z eit sell r.  fit r  Tiiherkulose,  vol.  xi..  No.  5)  has  drawn  attention 
to  the  fact  that  in  cases  of  tender  skins — especially  in  children, 
therefore — a  shght  obstruction  of  the  temporal  veins  is  to  be 
observed  in  tuberculosis  of  the  bronchial  glands,  manifested 
by  their  fulness  (on  one  or  both  sides),  or  by  the  serpentine 
shape  assumed   by  the  veins.     He  is  inclined  to  draw  from 
this  fact  the  conclusion  that  in  such  individuals  tuberculosis 
of  the  bronchial  glands  is  present,  and  he  even  goes  so  far  as 
to   indicate    the   site   of  the    diseased    glands    from    the    side 
affected.     This  latter  contention  could  only  be  based  on  a  few 
autopsies,  which,  however,  he  does  not  adduce.     Although  also 
the  other  proofs  for  the  maintenance  of  this   statement  are 
not  exactly  conclusive  (he  has  once  examined  school  children 
who  had  attracted  his  attention  by  their  temporal  veins,  and 
has  found  part  of  them  with  affections  of  the  apices,  and  others 
with  hereditary  connections),  and  though  his  observations  have 
not  been  sufficiently  extensive  to  prove  the  presence  of  tuber- 
culosis of  the  bronchial  glands,  I  yet  beheve  the  observation 
to  be  worth  consideration.     I  certainly  do  think  that   great 
significance  is  to  be  attached  to  the  conditions  of  the  veins 
of  the  thorax  and  neck  ;   also  in  tuberculosis  of  the  bronchial 
glands,  as  has  been  observed  by  Kronig  and  Naumann,  at  any 
rate    a   greater    significance    than    to    the    condition    of    the 
temporal  veins.     At  all  events,  the  observation  of  the  temporal 
veins  has  this  advantage,   that  in  any  child  the  existence  of 
venous  distension  can  be  determined  without  further  examina- 
tion, an  advantage    which  I  cannot    look    upon,  however,    as 
being  very  valuable. 

Although  the  pressure  on  the  veins  is  of  great  significance, 
a  still  greater  importance  must  be   attached  to  the  pressure 


DIAGNOSIS    OP    TUBERCULOSIS  175 

on  the  bronchus,  the  greatest  proof  being  a  combination  of 
symptoms  of  vein  pressure  with  those  of  bronchus  pressure. 
One  might  suppose  that  the  size  of  the  bronchi  in  this  region 
only  allows  very  consistent  and  large  tumours  to  exercise  any 
pressure  on  the  bronchus,  which  is  supported  by  strong 
cartilages.  But,  as  a  matter  of  fact,  this  is  not  the  case. 
The  bronchophony  specially  described  by  d'Espine  in  Geneva 
(Tuberculosis,  vi.,  1907,  No.  5),  a  change  in  the  vocal  fren)itus 
in  auscultation  called  "  chuchotement  "  by  the  French,  can  only 
be  explained  by  a  pressure  on  the  bronchus.  This  symptom 
can  be  observed  when,  during  auscultation  over  the  apex,  the 
patient  is  asked  to  pronounce  words  with  a  hissmg  sound  in 
a  low  but  distinct  voice. 

So  far  but  little  is  known  concerning  the  origin  of  bronchial 
breathing.  We  only  know'  that  it  appears  when  the  vesicular 
normal  type  of  breath  is  heard  in  large  or  small  regions — in 
infiltrations  of  a  pneumonic  and  more  frequently  in  those  of 
a  tuberculous  nature.  Since  bronchial  breathing  is  not  dis- 
cernible in  the  vesicular  sound  produced  by  normal  breathing, 
one  must  assume  that  the  bronchial  breathing  sound  produced 
by  the  air  normally  passing  through  the  bronchi,  is  either 
broken  up  in  the  pulmonary  vesicles  or  is  drowned  by  the 
other  sound. ^     Thus  an  infiltration  would  not  be  a  necessary 


'  In  this  waj'  we  can  understand  why  bronchial  breathing  and  broncho- 
phony are  employed  in  diagnosing  infiltration  of  the  apex.  Bronchopliony 
is  only  another  application  of  bronchial  breathing ;  in  bronchial  breathing 
one  discerns  the  sound  produced  by  the  entrance  of  the  air  into  the 
bronchial  tube  system,  unimpaired  by  the  sound  in  the  pulmonary 
vesicles  ;  in  bronchophony  the  sound  produced  in  the  larynx  is  heard  to 
resound  in  the  tubular  bronchial  system,  and  is  not  impaired,  since  no 
vesicles  are  found  in  the  infiltrated  part.  The  difference  in  the  methods 
consists  only  in  the  fact  that  by  telling  the  patient  to  speak  in  a  low  tone 
the  sound  is  formed  at  the  vocal  cords,  sounding  the  resonant  action  of 
mouth  and  nose. 

The  same  phenomena  cannot  so  easily  be  explained  in  the  case  of 
tuberculosis  of  the  bronchial  glands;  it  is  difficult  to  conceive  how  pressure 
on  the  bronchus,  apart  from  bronchial  breatliing,  can  possibly  bring  about 
bronchophony  over  the  sternum  without  infiltration  in  any  part  of  the  lung. 

In  order  to  prevent  over- valuation  of  the  clinical  method  of  examination, 
it  must  be  pointed  out  that  these  phenomena  (viz.,  bronchial  breathing 
and  bronchophony)  do  not  indicate  the  etiology  of  the  disease,  nor  do  they 
enable  us  to  arrive  at  a  definite  conclusion  concerning  the  condition  of  the 
part  of  the  lung  in  question,  since  in  the  healthy  individual  the  completed 
retractive  processes  produce  the  same  symptoms  as  the  acute  ones. 


176  THE  OPHTHALMIC  AND  CUTANEOUS 

factor  in  the  production  of  the  bronchial  breathing  sound, 
as  it  is  supposed  to  be  from  a  chnical  point  of  view  by  reason 
of  the  conclusions  chiefly  drawn  on  the  basis  of  bronchial 
breathing  ;  one  need  only  assume  a  displacement  and  com- 
pression of  the  lung  tissue.  The  fact  that  bronchial  breathing 
frequently  accompanies  lung  tumours,  and  especially  when 
there  is  pleuritic  exudation  without  affection  of  the  lung 
parenchyma,  can  only  be  explained  in  this  manner.  This 
last  mentioned  fact  is  frequently  ignored,  perhaps  because  the 
usual  explanation  of  bronchial  breathing  does  not  provide  for 
its  presence  in  cases  of  pleural  exudations. 

Bronchial  breathing  usually  accompanies  the  presence  of 
tumours  in  the  anterior  mediastinum ;  it  frequently  assumes 
an  almost  amphoric  character.  This  amphoric  breathing 
cannot  be  explained  in  any  other  way  than  by  assuming  a 
pressure  on  the  bronchus  by  the  tumour,  and  a  displacement 
of  the  mesial  lung  borders,  which  as  a  rule  cover  the  bronchus 
at  this  point.  Now  it  is  not  reallj''  remarkable  that  bronchial 
breathing  sounds  are  discerned  at  this  spot  under  pathological 
conditions,  but  it  is  peculiar  that  normally  pure  vesicular 
breathing  takes  place  at  this  spot,  the  chief  bronchus  being 
so  close  to  the  thoracic  wall.  Considering  the  acoustic 
phenomena  in  this  region,  one  is  quite  justified  in  assuming 
that  the  fine  vesicular  breathing  in  the  lung  borders  which 
cover  it  drowns  the  bronchial  breathing  sound,  although 
this  in  itself  really  is  much  louder,  so  that  it  cannot  any 
longer  be  discerned. 

In  the  case  of  mediastinal  tumours,  bronchial  breathing 
is  always  found  over  the  sternum,  especially  at  the  border 
between  the  body  and  manubrium  sterni,  and  is  of  very  great 
diagnostic  importance.  Although  Senator  takes  every  avail- 
able opportunity  to  point  to. the  existence  of  this  symptom,  so 
far  it  has  remained  practically  unknown. 

I  have  availed  myself  here  of  the  opportunity  to  refer 
extensively  to  these  symptoms,  not  merely  because  the 
diagnosis  of  mediastinal  tumours  is  connected  with  the  earlv 
diagnosis  of  pulmonary  diseases  frequently  requiring  considera- 
tion in  a  differential  diagnostic  direction,  but  chiefly  by  reason 
of  the  fact  that  tuberculosis  of  the  bronchial  glands  necessarily 
produces  identical  or  analogous  symptoms,  resulting  from 
identical  physical  conditions.  Personally,  I  have  had  a  good 
deal  of  child  material  at  my  disposal,  though  for  too  short 
a  time  to  gain  sufficient  experience  in  this  direction,  so  that 


DIAGNOSIS    OF    TUJiEHCULOSIS  177 

I  have  not  been  able  to  decide  this  question.  However,  I 
earnestly  advise  those  who  continuously  connnand  a  large 
amount  of  material  to  carry  on  these  diagnostic  investigations, 
especially  in  those  cases  in  which  the  diagnosis  of  tuberculosis 
of  the  bronchial  glands  has  been  definitely  determined  by  the 
Rontgen  method,  and  to  investigate  to  what  extent  the 
complexes  of  symptoms  of  venous  obstruction,  bronchophony, 
and  bronchial  breathing  are  found  over  the  sternum,  especially 
in  cases  where  the  local  tuberculin  diagnosis  indicates  the 
presence  of  a  tubercular  centre,  the  other  clinical  methods  not 
having  been  sufficiently  adequate  to  localize  this  centre. 

THE    STREAK   DIAGNOSIS. 

We  will  just  refer  to  the  "streak  diagnosis"  recently 
recommended  by  Franke  {Milnch.  vied.  Wochenschr.,  1907, 
No.  46).  He  observed  dilated  capillary  vessels  of  a  deep 
red  or  bluish  appearance  on  the  skin  over  the  apices.  He 
found  them  in  three-quarters  of  the  lung  cases,  although  no 
real  difference  could  be  observed  between  the  different  stages. 
In  healthy  individuals — that  is  to  say,  in  persons  who  are  not 
clinically  suspected  of  suffering  from  tuberculosis  — he  fountl 
them  in  25  per  cent.  In  cases  of  manifest  tuberculosis  this 
appearance  is  only  absent  when  the  pleura  costalis  has 
remained  absolutely  unaffected.  The  observation  does  not 
seem  to  me  to  be  altogether  justified. 

PERCUSSION    OF    THE    APICES    ACCORDING    TO    KKONIG. 

Seventeen  years  ago  Kionig,  in  his  article  "  Zur  Topo- 
graphie  der  Lungenspitzen  und  ihre  Perkussion "  {Bcrl. 
klin.  Wochenschr.,  1889,  No.  87),  published  a  method  which 
he  designated  as  the  topographical  percussion  of  the  apices. 
A.  Frtinkel  traced  the  origin  of  the  method  back  to  Seitz,  and 
especially  to  Ziemssen  (Leipzig,  1883,  clinical  lecture)  (see  the 
literature  dealt  with  by  Goldscheider,  Bed.  klin.  Wochenschr., 
1907,  No.  40).  In  1902  Kronig  republished  his  method  in 
the  Med.  Wochenschr.,  and  has  recently  (1907)  provided  us  with 
a  monograph  in  the  Deutsche  Klinik.  The  method,  there- 
fore, is  not  a  very  recent  one,  although  it  is  only  lately  that 
it  has  been  regarded  with  the  amount  of  interest  it  deserves. 
In  the  meantime  only  a  publication  by  Oestreich,  *'  Die  Per- 
kussion der  Lungenspitzen  "  {Zeitschr.  f.  klin.  Med.,  lb>99, 
vol.  35)  and  one  by  myself  {Deutsche,  med.  WocJienschr., 
12 


178 


THE  OPHTHALMIC  AND  CUTANEOUS 


1908,  No.  6),  "  Erfahrungen  mit  der  Perkussion  der  Lungen- 
spitzen  nach  Kronig,"  need  to  be  mentioned.  Oestreich  had 
tested  the  \method  experimentally  in  post-mortem  material, 
and  had  obtained  extremely  favourable  results.  He  has  been 
able  to  determine  the  presence  of  tubercular  centres  the  size 
of  cherries :  that  is  to  say,  if  they  were  not  too  far  removed 
from  the  surface. 

The  essential  part  of  Kronig's  methods,  it  seems  to  me, 
is  the  observation  that  from  the  point  of  view  of  percussion 
it  is  not  conducive  to  favourable  results  to  imagine  a  border 
at  the  top  of  the  apex,  but  that  it  is  much  better  to  project  the 
sound  departing  from  the  apex  as  a  broad  band  over  the 
shoulder-girdle.  This  does  away  with  the  upper  and  mesial 
borders  assumed  by  all  former  methods  of  percussion.  The 
Kronig  method  shows  very  clearly  that  it  is  easier,  more  to  the 
l^urpose,  and  productive  of  better  results,  if  light  percussion  is 


Fig.  5.^ — RepresectiEg  the  cocditions  existicg  in  strong  and  light  percus- 
sion, modified  according  to  Krunig.  a,  b,  Low  centre,  which  can  be  brought 
into  the  cone-shaped  sound  region  only  by  means  of  strong  percussion,  and 
can  be  recognized  by  ear  ;  c,  d,  superficial  apical  centre,  which  can  be  recog- 
nized only  by  weak  percussion — strong  percussion  would  produce  the  resonance 
of  too  great  an  amount  of  healthy,  full-toned  pulmonary  tissue. 


employed,  avoiding  the  resonance  of  the  deeper  regions  of  the 
apices,  and  not  endeavouring  to  define  the  upper  border  of  the 
lung.  It  is  quite  possible  to  define  this  border  :  lately  Gold- 
scheider  has  experimented  with  Kronig's  special  method  of  per- 
cussion, applying  the  softest  and  most  defined  percussion  ;  j^et 
it  would  seem  to  me  to  be  wiser  not  to  endeavour  to  fix 
the  exact  position  of  the  apex,  but  to  project  the  resonance 
of  the  lung  to  the  region  of  the  neck  in  front  (bordered 
by    the    sternocleido,    clavicle,     and    cucularis)    and    behind. 


DIAGNOSIS   OF   TUBERCULOSIS 


179 


The  sound-waves  in  this  manner  are  projected  in  a  way 
not  unlike  the  projection  of  Hght-rays  by  a  projection  lens, 
the  actual  conditions  prevailing  in  the  apex  being  trans- 
mitted on  to  an  enlarged  surface.  Now  it  is  true  that  the 
determining  of  the  upper  lung  border  constitutes  a  direct 
method,  whilst  percussion  of  the  apex  is  merely  an  indirect 
method  ;  but  this  is  not  necessarily  a  disadvantage.  Just  as 
we  frequently  prefer  the  use  of  a  lens  to  the  naked  eye,  so 
also  in  this  case  it  is  of  more  advantage  to  enlarge  the  minute 
surface  at  our  disposal  in  the  direct  method  of  investigation 
by  the  method  of  projection.  Refractions — which  in  direct 
percussion  of  the  apex,  by  determining  the  condition  of  its 
highest  point,  do  not  differ,  or  only  to  the  extent  of  a  few 
millimetres,  or  are  not  to  be  determined  at  all — showed,  when 
the  projection  method  was  applied,  a  distinct  narrowing  of 
the  band  which  passes  over  the  shoulder  in  front  and  behind, 
representing  the  projection  of  the  pulmonary  sound. 


Outlining  the  apex, 
according  to  Krouig 


Determining  the  con- 
dition of  the  apex, 
according  to  Gold- 
scheider. 


Fig.  6. — The  arrows  indicate  the  direction  cf  the  sound,  showing  the 
difference  between  Goldscheider's  and  Kronig's  methods  of  percussion  of 
the  apex. 


Those  of  my  readers  who  are  acquainted  with  both  methods 
are  not  in  need  of  any  further  elucidation  ;  those  who  have 
not  heard  of  them  will  ask  with  some  surprise  wherein  con- 
sists the  difference  between  the  production  of  sound  projec- 
tion and  the  method  of  determining  the  condition  of  the 
apex.  In  case  the  slight  percussion  is  employed  for  both 
no  real  difference  can  exist,  they  will  say,  and  both  methods 
ou<Tht  to  give  identical  results. 


180 


THE  OPHTHALMIC  AND  CUTANEOUS 


This  objection  is  apparently  justified,  and  the  actual  dif- 
ference between  the  two  methods  consists  only  in  the  different 
application  of  the  resonance  conditions  :  that  is  to  say,  in  the 
co-resonance  of  different  parts  of  the  lungs,  according  to  the 
direction  given  to  the  percussion.  The  figure  shows  better 
than  a  long  description  would  what  constitutes  the  difference 
in  the  application  of  the  two  percussion  methods. 

In  Goldscheider's  method  the  percussion  takes  place  on 
the  finger  and  from  above  downwards,  until  the  place  is 
arrived  at  in  which  there  is  a  full  pulmonary  sound.  Since 
naturally  the  apex  becomes  narrower  towards  the  upper  part 
of  the  cone,  difficulties  are  in  the  way  of  determining  the  exact 
limits.  In  the  method  of  Kronig  the  percussion  is  performed 
from  right  to  left  (mesial  to  lateral)  until 
the  place  is  found  where  the  sound-waves 
touch  the  pulmonary  tissues.  By  the  course 
of  the  sound-waves  produced  by  this  per- 
cussion it  is  not  merely  the  upper  part  of 
the  apex  which  serves  as  a  basis  for  the 
resonance,  but — since  the  cone  representing 
the  apex  becomes  thicker'going  downwards 
and  the  percussion  sound-waves  form  an 
angle  of  180''  instead  of  90',  as  is  the  case 
in  the  other  method — the  whole  of  the  upper 
part  of  the  lung  serves  as  a  resonator  for  the 
sound,  and  changes  in  the  sound  should  be 
present ;  and  in  this  manner  the  signs  not 
only  become  more  pronounced  through  the  percussion,  becom- 
ing adaptable  to  notation,  but  can  also  be  discerned  by  the  ear 
on  account  of  the  resonant  basis. 

Whatever  be  the  standpoint  taken  up  with  regard  to  these 
theoretical  attempts  at  explanation,  one  thing  is  certain  :  in 
healthy  individuals  sound  regions  are  obtained  by  means  of 
Kronig's  method  of  percussion  with  projection,  depicted  in  the 
figures,  in  which  the  region  designated  by  me  as  isthmus  is  at 
least  4  cm.  in  breadth. 

Kronig  recommends  percussion  with  the  finger  on  a  finger, 
rejecting  all  other  methods,  and  placing  great  value  on  the  co- 
activity  of  the  feeling  of  palpation  in  percussion  of  the  apex. 
However,  very  good  results  can  be  obtained  by  percussion  with 
the  hammer  on  the  finger,  the  palpation  of  the  finger  being 
frequentl}^  very  good.  The  results  of  percussion  can  be  com- 
plemented in  a  very  appropriate  manner  by  substituting  for  the 


Fig.  7.  —  Plexi- 
meter  for  percussion 
of  the  apex. 


DIAGNOSIS    OF   TUBERCULOSIS 


ISl 


palpation  a  self-constructed,  very  small  cii'cuhir  pleximeter, 
slipjhtly  bent,  which  controls  these  results.  One  might  even 
employ  Ziemssen's  wedge-shaped  pleximeter. 

To  employ  this  method  successfully,  one  should  have 
acquired  some  dexterity  in  applying  the  percussion  ;  in  that 
case  it  is  not  difficult  to  learn.  The  chief  rule  to  guarantee 
correct  results  consists  in  carefully  noting  to  apply  the  per- 
cussion exactly  along  the  lines  shown  in  the  figure.     If  the 


Fig.  8. — Position  of  the  apex,  accordiug  to  Goldscheider. 


Fig.  9. 


Fig.  10. 


Result  obtained  by  Krouig's  method  of  percussion  of  the  apex  in  health)' 
individuals  (schematized).  The  narrowest  part  (isthmus  of  the  apex,  according 
to  Michaelis  and  Wolff-Eisner)  is  at  least  i  cm.  in  breadth  on  either  side. 


finger  is  not  laid  on  exactly  parallel,  it  is  unavoidable  that  a 
part  of  the  finger  covers  the  projection  of  the  pulmonary 
sound,  whilst  another  part  is  situated  over  airless  tissues, 
and  thus  it  is  obvious  that,  through  the  co-resonance  of 
the  lung,  a  sound  is  also  produced  where  there  is  no  lung. 
Since  the  finger  possesses  a  certain  thickness  and  is  not  a 
mere  line,  the  same  thing  may  even  happen  in  a  percussion 
of  the  apex  properly  carried  out.     If  in  percussion  I  approach 


182  THE  OPHTHALMIC  AND  CUTANEOUS 

the  border  of  the  lung  in  a  parallel  manner — that  is  to  say, 
if  I  reach  the  border  of  the  band  produced  by  projection — 
a  moment  will  come  in  which  half  the  finger  is  situated 
on  the  lung  tissue,  whilst  the  other  half  is  resting  on 
tissue  where  the  lungs  are  not.  At  such  points  a  more  or 
less  full  pulmonary  sound  will  be  obtained.  The  proper 
border  in  this  case  is  so  situated  that  on  one  side  a  full 
lung  sound  is  obtained,  whilst  on  the  other  side  there  is 
a  deadened  sound.  This  point  is  found  by  gradually  mov- 
ing the  finger  up.  In  this  manner  the  border  of  the  lung 
may  be  defined  most  exactly.  The  differences  in  repeated 
investigations  of  the  same  individual  by  different,  though 
very  experienced,  investigators  do  not  amount  to  more 
than  ^  cm.  for  both  borders  together,  and  thus  only  ^  cm.  on 
each  side  ;  whereas  the  differences  to  be  reckoned  with  for 
pathological  purposes  amount  to  1  cm.  and  more. 

The  borders  of  the  apex  are  more  difticult  to  determine 
at  the  back,  because  here  percussion  has  to  take  place 
through  thick  layers  of  muscles,  and,  as  far  as  my  ex- 
perience goes,  it  is  easier  to  determine  any  changes  in 
front.  Yet  Kronig  attaches  as  great  an  importance  to 
determining  the  back  borders  as  the  front  ones.  It  seems 
as  if  he  regards  the  formation  of  all  projected  apical  lines 
obtained  by  percussion  to  be  of  value.  Naturally,  this  is 
quite  right,  although  it  is  not  very  easy  to  retain  the  im- 
pression and  to  note  it  down  in  writing.  We  recommend 
the  notation  only  of  peculiarities  (such  as  abnormal  bor- 
ders, absolute  and  relative  shortness  of  sound,  &c.)  and  to 
measure  the  so-called  apical  isthmus,  an  idea  introduced  by 
L.  Michaelis  and  myself.  The  apical  isthmus  is  the  narrow- 
est part  in  the  band,  passing  over  the  shoulder-girdle  as  the 
projected  pulmonary  sound.  This  narrowest  region,  as  a  rule, 
is  situated  3  cm.  above  the  clavicle.  We  measure  this  region 
in  centimetres,  and  in  the  history  of  the  disease  we  refer  to 
the  observation  as  the  breadth  of  the  isthmus  of  the  apex. 
The  measure  can  be  taken  most  exactly,  and,  if  referred  to, 
it  affords,  even  after  several  years,  a  view  of  the  condition  of 
the  apex. 

The  following  are  the  prevailing  symptoms  in  affections 
of  the  apex :  There  either  is  a  decrease  in  the  pulmonary 
sound — which  decrease  in  its  turn  is  either  absolute  or  rela- 
tive— or,  in  normal  cases,  the  pulmonary  sound  ceases  in  a 
sharp  line,  whereas  in  affections   of    the    apex,   especially  in 


DIAGNOSIS    OF   TUBERCULOSIS  183 

infiltrative  forms,  we  frequently  find  a  region  of  half  i)iil- 
monary  sound  between  absolute  lung  sound  and  absolute 
non-resonance.  In  these  cases,  of  course,  it  is  much  more 
difficult  to  determine  the  border  than  in  those  in  which  the 
somewhat  decreased  lung  sound  at  once  changes  into  non- 
resonance.  In  these  cases  the  absolute  and  relative  deter- 
minations of  the  sound  have  to  be  carried  out  separately. 
One  may  come  across  individuals  in  whom  the  absolute  pul- 
monary sound  has  completely  disappeared,  and  who  have 
only  a  relative  one  left.  These  cases  again  bring  us  to  others 
in  which  the  apex  has  not  become  any  narrower,  but  where 
the  sound  border  is  not  defined,  but  confused.  For  noting 
down  the  various  observations  I  recommend  the  following 
forms : — 

Healthy  apices  : — 


1     A     5  absolute  (5  relative)  sound  on 
1                  the  right. 

5  absolute  (5  relative)  sound  on 
the  left. 

This  would    mean  :    congruent    absolute  and  relative  pul- 
monary sound  ;  isthmus  of  the  apex,  5  cm.  in  breadth. 

B     5  (5)  on  the  right. 

5  (5)  on  the  left.     Borders  con- 
fused on  the  left. 

This  indicates  a  commencing  infiltration  of  the  left  apex. 

C     3   absolute    sound   (5   relative  5  (5)  on  the  left, 

sound)  on  the  right. 


Catarrh   of   the  right   apex  with  infiltration,  without   re- 
traction. 


D    2  (2)  on  the  right. 

5  (5)  on  the  left. 

Catarrh  of  the  right  apex  with  retraction. 

E     0  (2)'on  the  right.                                     5  (5)  on  the  left.                                     ' 

Catarrh  of  the  right  apex,  which  has  caused  strong  retraction. 

As  may  be  seen  from  the  examples,  it  is  very  easy  to 
detect  retractive  processes  by  means  of  percussion  of  the 
apex  ;    the  exudative-infiltrative   processes  without  retraction 


184 


THE  OPHTHALMIC  AND  CUTANEOUS 


are  somewhat  more  difficult  to  make  out.  Yet  no  other 
method  affords  facilities  in  this  direction  like  the  apical 
percussion  method.  In  order  to  recognize  the  last-  men- 
tioned cases  we  must  possess  the  faculty  of  perceiving 
sound,  without  which  the  finer  diagnosis  by  means  of  apical 
percussion  is  impossible.  The  foUowmg  example  may  show 
w^hat  this  method  is  capable  of  doing.  It  has  been  possible 
in  a  few  cases  of  pleuritis,  with  lymphocyte  exudations,  to 
determine  affections  of  the  apices  by  this  method,  whilst 
all  other  methods  in  use  before  the  discovery  of  the  local 
tuberculin  reactions  did  not  reveal  the  fact. 


Fig.  11. 

Commencing  infiltration  of  tlie 

right  apex  (deformed  mesial  border). 


Fig.  12. 
Catarrh  of  right  apex  with  strong 
retraction  (narrowing  of  the  abso- 
Ivite  sound). 


Fig.  13. — A  catarrh  of  the  right  apex  with  infiltration, 
without  retraction.  Observations  by  Krunig's  apical  percus- 
sion method  in  tuberculous  patients. 


I  should  like  to  point  out  that,  however  valuable  this 
method,  it  requires  to  be  complemented  by  others,  as,  for 
instance,  in  two  cases  which,  for  reasons,  had  to  be  very 
thoroughly  examined,  no   results   were   obtained  by  the  per- 


DIAGNOSIS    OF    TUBERCULOSIS  iH;") 

cussion  method,  althouf^h  tubercle  bacilli  were  found  in  the 
sputum.  Lately  also  Goldscheider,  as  mentioned  above,  has 
directed  his  attention  to  apical  percussion,  which  at  the  same 
time  shows  that  the  problem  is  not  lost  sight  of. 

He  endeavours  to  directly  determine  the  condition  of  the 
lungs,  employing  percussion  between  the  heads  of  the  sterno- 
cleido  mastoideus  in  an  exactly  sagittal  direction  (from  front 
to  back).  We  have  already  shown  that  a  determining  of  the 
condition  of  the  apices  is  a  possibility,  although  it  would 
be  extremely  difiicult  in  general  practice  by  reason  of  the 
small  surface  and  the  laws  of  resonance  mentioned  above. 

Goldscheider  raises  the  objection  against  Kronig's  apical 
percussion  that  in  the  sound  projection  also  the  deeper  parts 
of  the  lung  project  their  region  of  sound.  We  regard  this  as 
an  advantage,  since  it  facilitates  the  application  of  the  method, 
and  yet  gives  good  results.  Goldscheider's  method  may  be  the 
l)etter  one,  but  Kronig's  method  can  be  more  generally  applied 
if  one  does  not  lose  sight  of  the  rule  emphasized  by  Gold- 
scheider now,  and  by  ourselves  in  the  past,  to  always  apply 
the  percussion  parallel  to  the  probable  borders,  exactly  in 
a  downward  direction. 

Goldscheider  argues  against  Kronig's  isthmus  of  the  apex. 
The  conception  is  one  which  I  have  introduced  into  a  work 
of  Goldscheider's  department,  and  does  not  refer  to  the  sound- 
band  passing  over  the  shoulder,  but  to  the  narrowest  place 
in  the  projected  sound  region. 

The  PhtjHiolugicul  Heterotopy  of  the  Apex  and  tJie  Collapse 
Induration.  —  Kronig,  by  means  of  the  apical  percussion 
method,  has  discovered  two  new  processes  in  the  lungs  and 
has  designated  them  as  "  physiological  heterotopy  "  and 
"collapse  induration"  or  "atelectasis."  The  former  condition 
can  fairly  easily  be  recognized.  The  pulmonary  sound  projec- 
tion is  displaced,  the  sound  region  maintaining  the  same 
extension.  Although,  as  far  as  I  am  aware,  no  post-7nortent 
results  are  as  yet  at  our  disposal,  there  is  no  reason  to  doubt 
the  actual  occurrence  of  this  condition. 

The  diagnosis  of  the  collapse,  on  the  other  hand,  seems 
to  be  very  difdcult.  Also  in  the  early  stages  of  tuberculosis 
a  collapse  occurs  in  the  first  instance  by  the  displacement  of 
the  apical  bronchus,  and  the  advantage  of  the  apical  percus- 
sion lies  in  the  fact  that  it  enables  us  to  recognize  this  condi- 
tion of  the  apex  at  a  very  early  date. 

Kronig's  collapse,  which  rests  on  a  non-tuberculous  basis. 


186  THE  OPHTHALMIC  AND  CUTANEOUS 

is  usually  found  to  exist  on  the  right  side,  and  Kronig  explains 
this  fact  by  the  greater  extent  and  ramification  of  the  right 
side  of  the  bronchial  system.  According  to  etfusions  made 
by  means  of  Wood's  metal,  the  right  lung  contains  more 
bronchi,  whilst  in  the  left  is  found  more  lung  tissue.  This, 
says  Kronig,  causes  the  suctorial  capacity  of  the  right  side 
to  be  larger,  and  more  dust  enters  the  right  apical  bronchi, 
producing  infiltration.  This  conclusion  does  not  seem  to  me 
to  be  altogether  logical,  because  the  suctorial  capacity  is  con- 
nected rather  with  the  elastic  lung  tissue  than  with  the 
unchangeable  bronchi.  The  explanation  given  above  is  only 
admissible,  therefore,  if  no  differences  exist  in  the  mass  of 
lung  tissue,  the  suctorial  capacity  being  the  same  at  both 
hides,  and  if  in  this  case  the  dust  particles  more  easily  enter 
the  wider  tubes  of  the  left  side. 

Kronig  attributes  the  origin  of  the  process  to  an  obstruc- 
tion in  the  nasal  breathing.  In  the  explanation  given  by 
him,  however,  the  latter  seems  only  to  play  an  indirect  part 
when  the  infiltration  process  is  left  out  of  account.  It  would 
be  desirable  for  rhinologists  to  investigate  in  how  many  cases 
tuberculosis  is  found  to  exist  if  there  are  filtration  sounds. 
As  far  as  I  am  aware,  such  investigations  have  not  yet  been 
instituted. 

In  the  cases  with  collapse,  Kronig  excludes  the  possibility 
of  the  affection  being  of  a  tuberculous  nature — (1)  by  reason 
of  the  clinical  health  signs  of  the  patients  in  question  ;  ('2) 
because  the  process  does  not  show  any  tendency  to  progress  ; 
and  (3)  on  account  of  the  unaffected  state  of  the  comple- 
mentary sinus — that  is  to  say,  on  account  of  the  unobstructed 
respiratory  freedom  of  the  lower  borders  of  the  lungs.  These 
reasons  seem  to  him  to  be  so  concluisive  that  even  the  pre- 
sence of  tubercular  centres,  which  were  found  at  autopsy  in 
the  indurated  apex,  or  positive  tuberculin  reactions  could  not 
change  his  views  on  the  subject,  because  he  clearly  states  that 
by  accident  tubercle  bacilli  happened  to  have  entered  the 
induration  afterwards.^  In  his  discussion  on  the  subject  he 
employs  the  terms  "  clmically  healthy  "  and  "  bacteriologically 
diseased."  We  will  deal  with  his  three  reasons  one  after  the 
other. 

•  The  observations  made  by  Bliimel-Clarus  (Med.  Hiii.,  1907,  No.  50) 
seem  to  corroborate  Kronig's  views.  In  one  sanatorium  fourteen  cases 
of  pneumoniokoniosis  did  not  give  a  conjunctival  reaction  ;  five  of  these 
were  subcutaneously  injected  with  tuberculin,  and  none  gave  a  reaction. 


DIAGNOSIS    OF    TUBERCULOSIS  187 

The  clinical  state  of  health  does  not  contradict  the  possi- 
bility that  the  collapse  induration  may  have  had  a  tuber- 
culous origin  and  may  have  healed  up  perfectly  again,  aided 
by  the  indurative  character  of  the  affection  in  question.  This 
also  settles  point  two  ;  the  healed-up  centre,  of  course,  need  not 
expand.  Thus  only  point  three  is  left.  It  has  been  proven, 
and  as  a  matter  of  fact  it  is  of  diagnostic  importance,  that  if 
active  tuberculous  processes  are  present  in  the  lung,  the 
respiratory  elasticity  of  the  lung  borders  decreases.  I  quite 
agree  with  Kronig  that  too  little  attention  is  being  paid  to 
this  symptom  during  examination ;  but  I  am  not  certain  as 
to  whether  his  explanation  of  this  phenomenon  is  quite  correct. 
He  attributes  the  decrease  in  the  respiratory  elasticity  to  an 
adhesion  of  the  pleura  costalis  to  the  pleura  pulmonalis  in 
the  complementary  space,  to  which  the  toxin  is  supposed  to 
flow  from  the  apex,  accumulating  there  for  some  little  time. 
However  certain  the  fact  of  the  decreased  respiratory  elasticity, 
Kronig's  explanation  is  not  by  any  means  proven.  Kronig 
himself  admits  that,  on  account  of  the  infrequency  of  autopsies 
in  initial  cases  of  apical  catarrh,  we  can  lay  hands  on  only  a 
very  few  pathologico-anatomical  observations,  and  so  far  no 
attention  has  been  paid  to  this  supposed  process.  To  prove 
his  point  he  only  adduces  Schmaus,  who  has  found  adhesions 
between  the  pleura  costalis  and  pulmonalis  in  nearly  all  cases 
of  phthisis  (see  Kronig,  Deutsche  Klinik,  1907,  p.  650). 

It  seems  to  me  not  improbable  that  Schmaus  referred  to 
cases  of  phthisis,  that  is  to  say  to  pulmonary  tuberculosis  in 
the  third  stage,  and  not  to  initial  affections  of  the  apex.  And 
even  if  we  suppose  that  the  toxins  of  tubercle  bacilli  could 
bring  about  the  cohesion  of  the  pleural  layers,  we  do  not  under- 
stand how,  without  framing  elaborate  secondary  hypotheses, 
the  lymph  passage  of  the  pulmonary  centre  of  tuberculosis 
could  run  into  the  pleural  lymph-vessels  instead  of  into  the 
bronchial  glands.  For  this  to  happen  even  partiall}'  the 
pleura  would  have  to  play  a  part  in  the  affection  of  the  apex, 
and  such  a  partial  pleuritis  in  itself  would  explain  a  diminished 
respiratory  elasticity  of  the  lungs.  Whether  this  diminished 
respiratory  elasticity — known  in  the  Eontgen  figure  as  Wil- 
liams's phenomenon,  and  there  recognized  by  the  movements 
of  the  diaphragm — is  indicative  of  Nature's  effort  to  promote 
healing  by  putting  the  lung  at  rest  we  will  not  stop  to  deal 
with  in  this  connection,  the  more  so  since  in  the  therapy  of 
apical  affections  it  is  a  matter  of  dispute  what  constitutes  the 


188  THE  OPHTHALMIC  AND  CUTANEOUS 

best  cure  for  the  luno;,  rest  or  care,  or  on  the  other  hand 
breathing  exercises  with  forced  movements.^  However  that 
may  be,  after  the  healing  takes  place  there  is  no  reason  to 
further  limit  respiratory  movements  ;  the  respiratory  elasticity 
can  be  fully  regained  even  after  a  slight  and  favourable  pleuritis. 

But  for  the  moment  let  us  imagine  ourselves  altogether 
on  Kronig's  standpoint  in  regard  to  the  origin  of  the  cohesions 
in  the  complementary  space.  He  himself  admits  that  they 
only  occur  when  toxins  go  there  from  the  tubercular  centre 
in  the  lung :  that  is  to  say,  only  in  case  the  apical  lymph 
passages  are  not  obstructed. 

In  cases  that  take  a  favourable  course — that  is  to  say, 
where  the  tubercular  centre  has  been  completely  isolated  by 
infiltrative  changes — the  process  in  the  complementary  space 
referred  to  above  could  not  have  taken  place.  In  cases  with 
infiltrative  processes  of  so  chronic  a  nature  we  might  assume 
the  displacement  of  the  lymph  passages  and  the  perfect  isola- 
tion of  the  tubercular  centre  so  that  no  poison  can  reach  the 
body,  thus  causing  general  symptoms.  In  that  case,  according 
to  Kronig,  the  respiratory  elasticity  would  remain  unimpaired, 
and  this  important  objection  could  not  be  raised  against  the 
tuberculous  basis  of  the  induration  in  question. 

If  one  forms  a  mental  picture  of  the  great  frequency  of 
tuberculous  changes  in  the  human  organism — a  frequency 
wdiich  the  clinician  is  still  inclined  to  underrate,  and  of  which 
he  is  now  furnished  with  an  idea  by  the  local  tuberculin 
reactions  and  the  comparison  of  their  results  with  post-mortem 
examinations — one  comes  to  regard  all  chronic  infiltrative 
changes  in  the  lungs  with  suspicion,  at  any  rate  as  far  as 
the  etiology  is  concerned.  The  most  recent  investigations 
by  Ascher  concerning  the  connection  of  tuberculosis  with  the 
production  of  smoke  (and  dust)  further  supports  this  concep- 
tion. This,  however,  does  not  prevent  the  percussion  of  the 
apices  and  the  observation  concerning  the  respiratory  elasticity 
being  of  immense  value ;  these  methods  of  investigation  show 
that  such  a  tubercular  centre  has  healed  up,  the  knowledge 
of  w^hich  is  of  sufiicient  importance  for  doctor  and  patient 
alike.  These  explanations  are  not  intended  to  depreciate  the 
value    of    Kronig's   percussion   method — no    one    appreciates 


'  See,  in  Braner's  "  Beitriige  zur  Tnberkulose,"  the  modern  efforts  to 
heal  puhiionary  tuberculosis  hy  causing  and  maintaining  an  artificial 
pneumothorax  (Lexer,  Brauer,  and  manj-  others). 


DIAGNOSIS    OF    TUBEiiCULOSIS  189 

its  importance  more  than  I — but  their  purpose  is  to  show  that 
it  is  just  the  formation  of  such  a  method  whicli  creates  new 
problems,  which  can  only  be  solved  by  newer  methods.  In 
this  way  the  method  of  Kronig  has  created  the  two  new 
disease  pictures  of  heterotopy  and  collapse  induration,  and 
these  indicate  that  apical  percussion  is  destined,  together 
with  the  new  methods,  to  develop  to  its  fullest  extent  the 
science  of  clinical  diagnosis. 

Kronig  need  have  no  fear  that  my  new  methods  are  put 
forward  with  the  intention  of  obviating  the  necessity  of  the 
clinical  examination,  and  of  introducing  a  diagnosis  by  means 
of  the  reaction  alone.  All  those  who  have  followed  my  argu- 
ments will  be  aware  that  this  is  not  by  any  means  my  purpose; 
as  I  have  already  indicated  in  the  Introduction,  an  etiological 
diagnosis,  as  afforded  by  the  reaction,  is  not  a  localization 
diagnosis,  and  in  tuberculosis  it  matters  considerablj^  whether 
the  disease  affects  the  skin,  the  glands,  the  bladder,  or  the 
lungs.  The  reactions  merely  constitute  a  very  valuable  com- 
plement to  the  clinical  examination  methods,  and  they  are 
intended  to  direct  clinical  attention  to  such  cases  in  which 
there  is  no  clinical  suspicion  in  order  to  cause  all  clinical 
methods  to  be  applied.  The  cutaneous  and  conjunctival 
reactions,  therefore,  serve  to  separate  the  suspected  and  un- 
suspected cases. 

I  only  object  to  Kronig's  expression  "clinically  healthy," 
and,  in  opposition  to  this,  "  bacteriologicallj'  diseased."  The 
clinically  healthy  individual  is  not  bacteriologically  diseased, 
but  the  patient  who — in  Kronig's  sense — is  really  bacteriolo- 
gically diseased  is  either  a  carrier  of  bacilli  (in  infectious 
diseases)  or  he  is  clinically  suspect,  since  tuberculous  pro- 
cesses may  continue  for  a  long  time  without  showing  clinical 
symptoms.  Now  Kronig  applies  the  term  "  bacteriologically 
diseased  "  to  those  individuals  who  react  on  tuberculin.  Accord- 
ing to  our  theories,  the  capacity  of  the  body  to  react  on  tuber- 
culin does  not  indicate  a  disease,  but  only  that  the  body  is 
capable  of  producing  a  reaction  when  tubercle  bacilli  products 
are  encountered  ;  this  may  indicate  either  that  the  body  is 
engaged  in  a  battle  as  yet  unconcluded,  or  that  the  battle 
with  the  tubercle  bacilli  has  been  decided  in  its  favour, 
which  m  the  form  of  reactive  capacity  may  enable  the  body 
to  resist  a  new  attack  with  even  greater  chances  of  success. 
For  this  reason,  it  is  not  appropriate  to  designate  such 
reactive  capacity  of  the  body  as  "  bacteriologically  diseased"  ; 


190  THE  OPHTHALMIC  AND  CUTANEOUS 

I  do,  however,  admit  that  the  publications  of  writers  who 
employed  tubercuUn  for  diagnostic  pm-poses  justified  Kronig's 
theories,  and  that  it  is  only  my  standpoint  which  is  based  on 
a  rather  different  conception. 

AUSCULTATION. 

Auscultation  has  not  provided  the  science  of  early  diagnosis 
with  any  new  applications.  It  is  not  necessary  to  point  to 
its  significance  in  the  diagnosis  of  pulmonary  tuberculosis. 
At  one  time  this  method  was  decisive  in  diagnosing  the 
initial  stage  of  the  disease ;  since  the  introduction  of 
apical  percussion,  however,  it  takes  a  secondary  place.  In 
order  to  obtain  by  means  of  auscultation  the  fullest  possible 
results  it  is  desirable,  according  to  Kronig,  to  employ  this 
method  in  the  early  morning  after  having  brought  about 
a  retention  of  secretions  by  means  of  morphium.  Formerly 
Sticker  recommended  iodide  of  potassium  for  the  same  pur- 
pose ;  however,  Albert  Frankel  ("  Pulmonary  Diseases  ")  and 
Kronig  do  not  advocate  its  use. 

THE    MORPHOLOGICAL    EXAMINATION    OF    EXUDATIONS  :    THE 
SO-CALLED    CYTO-DIAGNOSIS. 

The  morphological  examination  of  exudations  is  of  very 
great  importance  in  the  diagnosis  of  tuberculosis,  especially 
by  reason  of  the  fact  that  frequently  the  exudations  appear 
before  any  other  manifestations  of  tuberculosis  are  visible, 
thus  frequently  allowing  of  an  early  diagnosis.  In  another 
part  of  this  work  we  have  dealt  with  the  significance  of  the 
lymphocyte  sputum  for  the  diagnosis  of  tuberculosis  ;  in  a 
similar  way  the  examination  of  pleuritic  exudations  has  long 
been  neglected. 

I  was  nearly  induced  to  apply  Ehrlich's  methods  of  blood 
histology  to  the  exudations  of  the  serous  skin.  One  might 
expect  to  arrive  at  altogether  new  results  in  this  way ;  and 
indeed  these  results  were  obtained  as  soon  as  the  matter  was 
essayed.  It  is  difficult  to  explain  why  such  investigations 
were  not  pursued  until  quite  recently.  One  was  satisfied  with 
examining  the  unstained  fresh  preparations,  or  at  the  utmost 
staining  the  object  with  Loffler's  methylene  blue,  the  chief 
purpose  being  the  discovery  of  bacteria.  Ehrlich,  in  a  few- 
cases  of  pleuritic  exudations,  has  employed  his  triacid  mixture, 
thus  discovering  the  so-called  pseudo-lymphocyte. 


DIAGNOSIS    OF   TUBERCULOSIS  191 

As  mentioned  before,  up  to  the  3'ear  189!>  the  principal 
efforts  in  examining  the  exudations  were  in  the  direction  of 
discovering  bacilH  and  of  procuring  sut'ticient  evidence  for 
diagnosing  a  pleuritic  carcinoma.  Furthermore,  our  investi- 
gations have  shown  that  only  in  very  exceptional  cases  it  is 
possible  to  diagnose  carcinoma  from  microscopic  examinations 
of  exudations,  by  reason  of  the  extraordinary  polymorphia  in 
the  epithelia  of  the  serous  cutis  in  exudations. 

At  the  same  time  very  clever  experiments  were  conducted 
to  distinguish  between  exudations  and  transudations,  espe- 
cially to  decide  the  question  which  of  the  exudations  have  to 
be  regarded  as  hsemorrhagic,  because  it  was  believed  that  the 
diagnosis  of  haemorrhagic  exudations  allowed  of  far-reaching 
diagnostic  conclusions. 

I  will  give  a  short  liistorical  epitome  of  its  further  develop- 
ment on  account  of  the  great  similarity  between  this  and  the 
history  of  the  conjunctival  reaction. 

In  the  year  1898  the  Berlin  Medical  Faculty  invited  a 
prize  essay  on  the  microscopical,  bacteriological,  and  chemical 
examination  of  pleura  exudations.  I  participated  in  the  com- 
petition, which  had  to  be  completed  on  May  1,  1899.  In  my 
investigations  I  had  discovered,  to  my  great  astonishment,  that 
in  tuberculous  exudations  lymphocytes  are  constantly  found  ; 
that  tuberculous  exudations  are  characterized  by  this  fact, 
and  that  they  can  be  readily  distinguished  from  other  exuda- 
tions;  and  that  at  the  same  time  a  diagnostic  significance 
was  to  be  attached  to  this  discovery.  I  could  hardly  under- 
stand how  it  was  that  before  me  nobody  seems  to  have  made 
the  same  observations,  and  on  research  I  found  that  these 
facts  were  not  once  referred  to  in  the  whole  of  the  litera- 
ture. I  showed  the  preparation  at  the  time  to  Leonor 
Michaelis,  who  confirmed  the  accuracy  of  my  observations. 
Nine  years  later  I  was  equally  surprised  to  find  that  the 
presence  of  lymphocytes  in  the  sputum  had  in  a  similar 
way  been  overlooked  by  all  investigators. 

The  prize  was  awarded  to  another  author,  since  Gerhardt 
seems  to  have  regarded  my  observations  as  erroneous.  Also 
Professor  Franz  Konig — in  whose  laboratory  m}^  work  had 
originated,  though  quite  independent  of  his  supervision — 
disregarded  the  diagnostic  significance  of  the  discovery,  and 
after  having  originally  accepted  the  work  for  a  chirurgical 
journal  (in  a  letter  of  August  30,  1899),  he  reversed  his 
decision  a  vear  later  in  the  following  communication  : — 


192  THE  OPHTHALMIC  AND  CUTANEOUS 

"  March  10,  1900. 
"  Grave  doubts  have  arisen  in  my  mind  concerning  the 
accnracy  of  the  whole  theory,  but  in  any  case  I  must  say  that 
the  cases  on  which  you  have  been  working  have  been  chosen 
so  unfortunately,  or  have  been  reported  to  you  in  such  a  way, 
that  the  whole  matter  appears  in  a  different  light,  &c." 

Already  on  August  30,  1899,  he  had  written  as  follows  : — 
"  You  are  in  the  extraordinary  position  of  having  had  before 
you  exudations  containing  but  few  bacteria,  and  I  regret  that 
you  have  not  at  the  same  time  examined  my  empyema.  .  .  . 
This,  however,  may  not  allow  you  to  see  in  this  the  lack  of 
result  of  your  experiments." 

Professor  Franz  Konig  has  distinctly  given  me  permission 
in  writing  (May  25,  1905)  to  make  use  of  these  letters. 

A  year  later  (June,  1900)  Vidal  (and  Kavaut)  in  Paris 
announced  the  same  discoveries.  Although  at  the  very  first 
notice  of  this  publication  which  came  to  my  knowledge  I 
communicated  with  him  on  my  own  discoveries,  the  written 
reply  to  which  is  in  my  possession,  he  has  never  mentioned 
ray  independent  observations  in  a  single  instance,  nor  the 
theoretical  conclusions  concerning  the  active  lymphocytosis, 
the  movability  of  the  lymphocytes,  kc,  based  upon  them. 
From  1900  to  1902  articles  on  the  cyto-diagnosis  filled  the 
medical  journals  to  the  same  extent  as  is  the  case  nowadays 
with  those  on  the  ophthalmic  diagnosis,  and,  being  at  the  tmie 
a  mere  student  without  connections,  it  was  impossible  for  me, 
till  1901,  to  publish  the  discoveries  which  I  had  made  a  year 
before  Vidal. 


■\  \'The  Technique  of  tlie  Examination  of  the  Pleura  Exuda- 
tions.— The  examination  of  the  exudations  by  means  of  the 
most  refined  hsematological  methods  presents  some  technical 
difficulties  ;  these  may  sometimes  be  so  great  that  the  examina- 
tion is  altogether  fruitless.  The  value  of  such  investigations,  of 
course,  can  only  be  judged  in  so  far  as  they  produce  positive 
results.  In  the  examination  of  the  blood  one  always  works 
with  cells  taken  fresh  from  the  body,  and  never  with  the 
generated  cells,  which  are  never  found  in  the  circulation  in 
normal  cases.  The  cells  of  the  exudations,  on  the  other  hand, 
have  frequently  been  outside  the  circulation  for  weeks  ;  they 
are  dead,  and  subject  to  all  kinds  of  harmful  influences.  Even 
if   we  assume  that  their  presence  in  the   exudation  does  not 


DIAGNOSIS   OF   TUBERCULOSIS  193 

damage  the  cells,  yet  their  physiological  death  takes  place 
within  the  exudation  instead  of  in  the  spleen,  the  marrow  of 
the  bones,  &c.  We  know  that  the  granules  of  the  leucocytes, 
especially  those  that  are  neutrophile,  represent  the  most  labile 
part  of  the  cells  which  it  is  most  difficult  to  stain.  We  are, 
therefore,  not  surprised  to  find  that  the  representation  of  the 
neutrophile  granules  in  exudations  is  very  often  unsuccessful. 
The  formation  of  the  nucleus  allows  us  to  easily  recognize 
the  polynuclear  leucocytes  ;  but  in  exudations  there  are  tivo 
processes  which  complicate  the  diagnosis. 

The  cells,  where  not  fixed  at  once,  may  contract  to  such 
an  extent  that  they  assume  the  appearance  of  lymphocytes,  the 
nucleus  having  a  globular  appearance  on  account  of  the 
contraction.  Or,  on  the  other  hand,  the  nuclei  may  swell  to 
such  an  extent  that  a  similarity  to  lymphocytes  is  produced 
in  this  manner.  A  process  in  which  the  polynuclear  cell  really 
acquires  more  nuclei  is  more  rare,  but  yet  of  importance.  In 
that  case  the  cell  divides  into  several  parts,  the  so-called 
pseudo-lymphocyte  formation. 

It  is  important  to  know  of  the  existence  of  these  processes, 
since  when  diagnosing  the  presence  of  lymphocytes  in  the 
exudation  very  important  diagnostic  conclusions  are  incident- 
ally arrived  at  ;  for  this  reason  one  must  be  acquainted  with 
the  kinds  of  cells  with  which  they  might  be  confused.  The 
pseudo-lymphocytes  may  be  confused  with  nucleated  red  blood- 
corpuscles  ;  even  Vidal  has  fallen  into  this  error;  but  in  order 
to  avoid  this  mistake  one  need  only  think  that  it  is  impossible, 
if  the  blood  is  normal,  for  nucleated  red-blood  corpuscles  to 
be  present  in  exudations. 

They  may  also  be  confused  with  lymphocytes.  This  is  on 
account  of  the  round  nucleus,  which  is  surrounded  by  a  con- 
centric border  of  protoplasm  ;  in  most  cases,  however,  the 
greater  breadth  of  this  border  in  pseudo-lymphocytes  prevents 
confusion.  Fortunately  the  pseudo-lymphocytes,  as  is  clear 
from  their  origin,  are  chiefly  found  in  exudations  of  the  poly- 
nuclear type,  so  that  the  character  of  the  exudation  is  easily 
understood,  since  there  are  but  few  cells  which  could  give 
rise  to  confusion.  One  has  to  note  the  presence  of  single 
neutrophile  granules  in  the  triacid  method  of  staining,  and 
also  the  result  obtained  with  Pappenheim's  pyronin-methyl 
green  stain. 

Eosinophil  cells  are  rarely  found  in  exudations  and  have  no 
diagnostic  significance  ;  the  same  may  be  said  of  giant  cells. 
13 


194  THE  OPHTHALMIC  AND  CUTANEOUS 

According  to  Ehrlich,  the  lymphocytes  are  distinguished 
by  the  absence  of  granules.  Although  Michaelis  and  myself 
have  described  the  presence  of  azure  granules  in  lymphocytes, 
this  does  not  impair  the  diagnostic  significance  of  the  absence 
of  granulation  in  most  other  methods.  Since  the  other  leuco- 
cytes in  exudations  frequently  do  not  any  longer  contain 
visible  granules,  and  since  degenerative  processes  occur  in 
leucocytes  (karyorrhexis  and  karyolysis,  pycnosis),  the  diagnosis 
of  lymphocytes  is  not  always  simple. 

It  is  v^'ell  to  employ  a  number  of  different  methods  simul- 
taneously in  the  investigation,  especially  in  those  cases  in  v^hich 
the  nature  of  the  cells  in  question  is  doubtful  (hsematoxylin- 
eosine,  triacid,  Loffier's  methylene  blue,  Pappenheim's  pyronin- 
methyl  green  method,  May-Griinwald's  stain  and  the  Homan- 
owski  method ;  occasionally  the  glycogen  staining  with  iodium 
vapour  and  the  vital  staining  may  give  further  results).  We  have 
already  mentioned  that  the  epithelia  in  exudations  have  a  very 
polymorph  nature,  and  may  assume  the  most  peculiar  shapes. 
According  to  Ehrlich,  they  too  are  frequently  confused  with 
the  large  mononuclear  cells  of  the  blood,  as  also  by  Vidal  and  a 
great  number  of  his  pupils.  These  cells  are  principally  found 
in  metapneumonic  and  rheumatic  exudations.  Vidal  lias 
pointed  out  that  in  ordinary  tubercular  pleuritis  these  cells 
do  not  occur  at  all,  or  very  rarely. 

In  many  cases  the  albumin  contained  in  the  exudations 
hinders  a  thorough  investigation,  causing  an  intense  staining 
of  the  background.  It  would  be  well  to  get  rid  of  the  albumin 
by  centrifugalizing  the  exudation  and  by  pouring  off  the  whole 
of  the  remaining  liquid  which  contains  the  albumin;  then  a 
physiological  solution  of  common  salt  is  added,  the  sediment 
is  disturbed,  the  centrifuge  is  again  applied  and  the  sediment 
is  brought  on  to  the  cover-glasses.  Since  in  a  number  of 
investigations,  especially  if  giant  cells  be  present,  the  addition 
of  water  should  be  avoided,  it  is  well  to  always  prepare  a  few 
cover-glasses  with  the  exudation  without  the  addition  of  water. 

In  preparing  the  slides  one  should  remember  a  frequently 
neglected  rule  which,  for  blood  preparations,  is  essential.  The 
cover-glasses  should  be  provided  with  but  a  small  amount  of 
liquid,  so  that  the  cells  may  dry  easily  and  no  damage  be  done  to 
their  morphological  structure  by  a  slow  process  of  drying, 
which  would  cause  more  difficulties  in  the  diagnosis. 

Summary. — In  summarizing  the  results  of  the  examination 
of  exudations,  we  may  distinguish  between  acutely  infectious 


DIAGNOSIS    OF    TUBERCULOSIS  195 

and  chronic  exudations.  If  50  per  cent,  or  more  lymphocytes 
he  found,  one  may  safely  diagnose  tiiberculosis.  Whatever  has 
been  said  on  this  subject  in  the  hterature  has  not  in  the 
least  affected  the  final  results.  As  previously  mentioned,  the 
accumulation  of  lymphocytes  in  exudations  is  not  charac- 
teristic for  tuberculous  processes  alone.  Lymphocytes  are 
also  found  in  spinal  fluids  in  paralysis,  tabes,  &c.  But  these 
diseases  can  hardly  be  confused  with  tuberculosis,  and  especially 
in  the  pleura  no  process  has  become  known  in  which  lympho- 
cytes accumulated  in  the  pleura  to  any  extent.  Strauss,  in 
the  Charite  Annals  of  1902,  mentions  the  discovery  of  a  lympho- 
cyte exudation  in  a  patient  who  did  not  react  on  a  diagnostic 
tuberculin  injection.  It  is  quite  possible  that  this  exudation 
was  not  tuberculous,  notwithstanding  the  presence  of  the 
lymphocytes.  On  the  other  hand,  it  may  also  be  possible 
that  the  cells  were  mistaken  for  lymphocytes  in  one  of  the 
ways  described  above,  which  may  happen  even  to  the  expert. 
Finally,  the  individual  in  question  might  not  have  reacted  on 
the  tuberculin  injection  even  if  he  had  been  tuberculous,  the 
actual  possibility  of  which  has  been  frequently  referred  to  in 
the  course  of  this  work. 

One  word  more  concerning  the  manner  in  which  these 
investigations — which,  according  to  the  description,  may  seem 
to  be  somewhat  protracted  and  troublesome — are  carried  out. 
Ih  order  to  obtain  results  of  scientific  value  it  is  desirable 
that  for  each  case  a  great  number  of  different  methods  should 
be  employed.  As  a  rule,  staining  wdth  Loffler's  methylene 
blue  suffices  to  form  a  perfectly  decided  diagnosis  in  cases  of 
distinct  lymphocyte  exudations.  In  practice,  this  method  at 
the  same  time  is  so  simple  that  I  can  recommend  its  universal 
application. 

THE    PROTEOLYTIC    FERMENTATION    OF    EXUDATIONS,    &C. 

We  will  refer  to  another  method  giving  results  almost 
identical  with  those  obtained  in  the  morphological  examination 
of  exudations.  Although  the  results  are  somewhat  less  decisive, 
on  the  other  hand,  the  application  of  this  method  is  very 
much  easier,  and  for  this  reason  it  may  be  employed  for 
quickly  discerning  between  tuberculous  and  other  ulcerations. 

The  process  consists  in  bringing  the  exudations  to  be 
examined  on  to  (coagulated)  albumin  (sheep  serum,  bovine 
serum,  &c.)  ;     non-tuberculous  exudations  effect  a  dissolution 


196  THE  OPHTHALMIC  AND  CUTANEOUS 

of  albumin  through  peptonization  as  a  result  of  proteolytic 
fermentation,  whilst  tubercular  exudations  and  tuberculous 
pus  do  not  cause  the  albumin  to  liquefy. 

The  test  is  carried  out  at  a  temperature  of  55^  C,  in  order 
to  prevent  a  growth  of  other  l^acteria  which  may  be  contained 
in  the  exudation,  so  as  to  avoid  liquefaction  through  bacterial 
enzymes. 

The  ixiethod  may  be  regarded  as  an  indirect  one,  and  is 
based  on  the  different  amounts  of  peptonizating  ferments  con- 
tained in  the  various  types  of  leucocytes.  We  are  dealing  here 
with  conditions  analogous  to  those  observed  in  staining  with 
guaiacum  blue.  It  is  well  know^n  that  the  granulated  leuco- 
cytes produce  a  bluish  tinge,  whilst  the  non-granulated  cells, 
the  lymphocytes,  do  not  possess  this  propert3^  In  the  same 
way  the  bone  marrow  gives  the  guaiacum  a  blue  tinge  in 
myeloid  leucocythaemia,  whilst  the  cells  of  lymphatic  leucocy- 
thfpmia  do  not  have  this  effect. 

There  are  other  methods  for  determining  the  contents  of 
pus  in  proteolytic  fermentations,  and  for  distinguishing  between 
tuberculous  and  other  ulcerations.  If  tuberculous  pus  is 
brought  into  Millon's  reagent,  a  strong  thin  membrane  is 
formed,  which  does  not  give  a  colour  reaction,  whilst  non- 
tuberculous  pus  produces  a  red  tinge.  This  test  corresponds 
with  the  biuret  test,  which  is  negative  in  tuberculous  pus  and 
positive  in  all  other  substances.  (Miiller  and  Jochmann, 
Miinch.  med.  Wochenschr.,  1906,  No.  29;  Kolaczek  and  Miiller, 
Deutsche  med.  Wochenschr.,  1907,  Nos.  7  and  17.) 

However,  tuberculous  pus  produces  a  negative  result  in  the 
biuret  test  onl}^  when  the  affected  spot  has  not  before  been 
treated  with  iodoform. 

This  statement  at  the  same  time  constitutes  a  criticism 
on  the  process.  From  studies  in  cyto-diagnosis  we  know 
that  in  tuberculosis  lymphocytes  are  predominant,  and  since, 
according  to  our  experience,  the  lymphocytes  are  lacking  in 
enzymes,  we  can  understand  why,  in  processes  in  which  lympho- 
cytes govern  the  disease  pictures,  those  reactions  which  are 
produced  by  ferments  are  negative.  Now,  if  in  a  tubercular 
process,  from  whatever  cause,  an  accumulation  of  leucocytes 
is  produced — for  instance,  bj''  injecting  iodoform  —  all  these 
ferment  reactions  will  be  positive.  The  coagulated  serum 
fluidifies ;  Millon's  reagent  produces  a  red  tinge,  and  the 
biuret  test  becomes  positive.  From  this  we  may  conclude 
that    only   the  absence   of   ferment    reactions    has   diagnostic 


DIAGNOSIS    OF    TUBERCULOSIS  197 

significance,  whilst  a  positive  result  may  very  well  occui-  in 
tuberculous  affections  if  an  ordinary  leucocytosis  is  produced 
by  chemical  means  or  by  mixed  infection. 

Nor  does  the  negative  result  prove  anything  definite,  and 
it  is  obvious  that  a  greater  significance  is  to  be  attached 
to  the  morphological  investigation,  since  the  predominance  of 
lymphocytes  enables  us  to  draw  diagnostic  conclusions,  which 
cannot  be  obtained  in  the  ferment  reaction,  because  the  fer- 
ment reactions  are  negative  only  when  hardly  any  perfect 
leucocytes  are  present.  At  any  rate,  this  very  easy  method 
may  be  employed  as  a  control  to  other  methods. 

INOSCOPY. 

The  method  of  inoscopy^  is  one  which  is  intended  to 
facilitate  the  ascertaining  of  the  presence  of  bacteria  in  an 
exudation  or  a  transudation,  especially  of  tubercle  bacilli,  by 
making  use  of  spontaneous  fibrine  coagulations.  To  ascertain 
whether  tubercle  bacilli  are  present  in  an  exudation  is  some- 
times so  difficult  that  in  cliiiical  science  the  following  phrase 
has  frequently  been  employed  :  "  An  exudation  without  bacilli 
points  to  a  tubercular  etiology."  This  was  on  account  of  the 
fact  that  bacilli,  especially  tubercle  bacilli,  were  very  rarely 
found  in  exudations. 

Recently,  in  a  fairly  large  number  oi  cases,  tubercle  bacilli 
have  been  found  in  exudations  in  animal  experiments  on  guinea- 
pigs  ;  negative  results  of  the  experiments,  however,  do  not  prove 
anything  definite,  because  it  is  quite  possible  that  the  virulence 
of  the  tubercle  bacilli  may  have  become  impaired.  Apart  from 
this  the  method  in  question  is  not  very  practicable,  since  results 
are  obtained  onlj'  after  some  weeks. 

By  methods  of  crushing  the  glands  and  injecting  tuber- 
culin a  few  days  after  the  injection  of  the  suspected  fluid,  as 
previously  described,  more  rapid  results  may  be  obtained  in 
animal  experiments,  though  they  are  not  always  absolutely 
reliable. 

The  method  of  centrifugali^ing  the  exudations  is  frequently 
unsuccessful  because  the  few  bacilli  are  contained  in  a  viscous 


'  This  interesting  method  has  lately  been  neglected  because  it  did  not 
provide  investigators  with  safticiently  favourable  results.  Its  theoretical 
basis,  hovi^ever,  is  good,  and  in  scientific  investigations  in  which  all 
methods  are  applied  to  elucidate  problematic  disease  pictures  it  should 
certainly   be  emploj'ed. 


198  THE  OPHTHALMIC  AND  CUTANEOUS 

fluid  of  a  fairly  high  specific  weight,  so  that  in  centrifugaliza- 
tion  they  are  not  precipitated.  Coagulation,  on  the  other 
hand,  fully  purifies  the  exudation  of  all  morphotic  constituents, 
which  may  be  seen  from  the  fact  that  Jousset,  for  instance, 
after  injecting  the  coagulated  substance  into  animals,  obtained 
as  many  positive  (infection)  results  as  Dumany,  who  injected 
the  coagulated  substance  together  with  the  serum. 

Now  Jousset  gets  at  the  bacilli  by  artificially  dissolving  the 
coagulated  substance.  After  various  experiments  with  alkalies, 
&c.,  he  concluded  that  the  best  process  was  the  artificial 
digestion,  according  to  the  following  recipe  : — 

Pepsine  (s.  d.)     ..      1 — -2  gr.v  This  liquid  substance  keeps  good  from  three 

Glycer.                     )                   I  to  four  weeks.     It  keeps  intact  the  leuco- 

Acidi  hydr.  (s.  d.)  [                    -  cyte  nuclei  and  the  bacteria,  and  only  par- 

Fluornatrium      ..         3'0      |  tially  destroys  the  virulence  of  the  tubercle 

Aqua  dest.            . .  1,000-0     ^  bacilli. 

The  coagulated  substance  has  to  be  thoroughly  cleansed  by 
means  of  water,  because  if  serum  is  present  the  digestion  is 
very  much  slower.  (This  must  take  place  at  a  temperature 
of  38°  C.)  Shake  every  half-hour ;  the  process  is  terminated 
in  two  to  three  hours.  Instead  of  bringing  the  mixture  into 
the  thermostat,  one  may  heat  it  for  a  short  time  in  a  water 
bath  at  a  temperature  of  50"  C.  The  mixture  is  now  centri- 
fugalized,  and  the  precipitation  is  used  for  streak  preparations. 

For  purposes  of  investigation  it  is  best  to  employ  coagulated 
substance  of  several  hundred  cubic  centimetres  of  exudation. 

The  inoscopy  of  the  blood  is  performed  in  a  similar  way, 
the  only  difference  being  that  directly  after  puncture  the  blood 
is  brought  into  150  to  200  c.cm.  of  sterile  water. 

Fluid  substances  which  cannot  coagulate  (urine,  transuda- 
tion of  ascites,  &c.)  are  made  to  do  so  by  adding  the  blood  of 
horses.  The  results  obtained  by  this  method  are  as  follows  : — 
In  twenty-three  pleura  exudations,  seventeen  of  which  were 
procured  from  patients  not  suspected  of  tuberculosis,  Jousset 
found  tubercle  bacilli  in  each  case.  In  twelve  exudations  of 
the  peritoneum,  the  etiology  of  which  was  unknown,  he  found 
eight  with  tubercle  bacilli,  of  which  three,  according  to  the 
clinical  examination,  &c.,  had  been  diagnosed  as  alcoholic 
cirrhosis  of  the  liver.  Autopsy  revealed  tuberculous  changes 
in  each  of  these  last  three  cases.  In  two  cases  of  acute 
tuberculosis  and  in  three  of  subacute  tuberculosis  he  found 
tubercle  bacilli  in  the  blood  ;  similarly,  in  two  cases  of 
arthritis  he  found  gonococci. 


DIAGNOSIS    OF    TUBERCULOSIS  199 

Already  in  the  living  mdividuiil  a  process  analogous  to 
coagulation  is  supposed  to  occur,  and  probably  constitutes  an 
automatic  defence  on  the  part  of  the  organism.  The  exuda- 
tions containing  the  greatest  amount  of  fibrine  substance 
probably  contain  the  fewest  bacilli.  The  number  of  bacilli 
varies  to  such  an  extent  that  sometimes  thousands  of  them 
are  found,  and  sometimes  only  a  few  after  a  prolonged  search. 
If  the  number  of  bacilli  is  not  very  large  they  are  generally 
found  free,  although  sometimes  they  are  grouped  round  a 
leucocyte  nucleus,  round  which  they  had  been  grouped  also 
before  the  digestive  process  had  taken  place,  and  where  they 
have  remained,  although  the  protoplasm  had  been  dissolved  in 
the  process  and  only  the  nucleus  had  been  left. 

As  to  their  staining  capacity,  we  may  say  that  the  bacilli 
of  the  exudations  are  easily  damaged  when  unstained,  and  for 
this  reason  unstaining  has  to  be  carefully  proceeded  with. 
The  author  believes  that  this  fact  is  not  due  to  the  digestive 
process,  but  is  a  result  of  their  stay  in  the  pleuritic  exudation. 

The  method  has  the  advantage  of  directl}'^  showing  the 
tubercle  bacilli  present.  The  direct  bacteriological  examina- 
tion of  the  exudations  has  been  neglected  up  to  the  present 
only  on  account  of  the  great  number  of  unsuccessful  results. 
The  inoculation  of  guinea-pigs  has  this  advantage  over  ino- 
scopy,  that  to  some  extent  it  gives  an  idea  as  to  the  degree 
of  virulence  of  the  bacilli  in  an  exudation,  while  inoscopy 
does  not.  Under  certain  circumstances  it  ma}^  be  very  im- 
portant to  know  whether  tuberculosis  is  very  active  or  less 
so.  For  this  reason  the  combination  of  inoscopy  with  the 
inoculation  of  guinea-pigs  may  be  regarded  as  a  good  method 
for  the  examination  of  exudations  as  to  the  presence  of 
tubercle  bacilli.  As  far  as  the  urine  is  concerned,  the  diffi- 
culty of  distinguishing  between  pseudo-tubercle  bacilli  and 
tubercle  bacilli  remains,  and  therefore  the  method  in  question 
is  of  value  only  in  some  cases. 


200  THE    OPHTHALMIC   AND   CUTANEOUS 


LITERATURE. 

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DIAGNOSIS   OF   TUBERCULOSIS  201 

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10  et  27  Juillet,  1907. 


•202  THE    OPHTHALMIC    AND    CUTANEOUS 

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77.  Finger  und  Landsteiner.      Wien.  klin.  Wochenschr,  1904-1907. 

78.  Forlaniui.     "  Zur  Behandluug  der  Lungeuschwiudsucht  durch  kiinstlich 
erzeugten  Pneumathorax,"  Deutsche  med.   Wochenschr.,  1906,  Nr.  35. 

79.  Le  Fort.     Presse  med.,  13  Juillet,  1907. 

80.  Francke.       "  Gefassstreifen,    ein    Erkenuungsmittel    der    beginnenden 
Schwindsucht,"  Milnch.  mfd.  Wochenschr.,  1907. 

81.  Francke,  Karl.     "  Die  Orthodiagraphie,'"    Miincheu,   J.  F.    Lehmann, 
1906. 

82.  Franke,    E.      "  Uber   Ophtbalmoreaktiou    bei   Tuberkulose,"    Deutsche 
med.   Wochenschr.,  Nr.  48,  1907. 

83.  Praukel,  A.     "  Spez.  Patbologie  und  Therapie  der  Lungenkraukbeiten," 
Urban  u.  Scbwarzenberg,  1904. 

84.  Fuchs.     "  Lehrbuch  der  Augeuheilkunde." 

85.  Gaudier  (Lille).     Presse  medicale,  13  Juillet,  1907. 

86.  Geugou.     Compt.  rend.  Acad,  des  Sciences.  Paris,  3  Aout,  1903. 

87.  Goldscheider.     "  Orthoperkussion,'"  Deutsche   med.    Wochenschr.,  1905, 
Nr.  9  u.  10. 

88.  Grashey.     "Atlas   typischer   Rontgenbilder  von  normalen  Menscben," 
Miinchen,  Lehmann,  1905. 

89.  Grassberger  und  Schattenfroh.      Wie7i.  klin.  Wochenschr.,  1907. 

90.  Grasset  et  Rimbaud.     "  Ophtalmo-reaction  a  la  tuberculine,"  Province 
medicale,  13  Juillet,  1907. 

91.  Grasset  et  Vedel.     Acad,  de  Medecine,  25  Fevr.,  1896. 

92. "Discussion  sur  la  reaction  a  la  tuberculine  ;    I'emploi  de  la 

tuberculine  pour  le  diagnostic  de  la  tuberculose,"  Soc.  vu'd.  des  Hapitaux,  7,  14, 
21,  28  Juin,  1907. 

93.  Griffon.     "Relations  du  purpura  infantile  a  forme  pseudo-peritoneale 
avec  la  scarlatiue,"  Soc.  mi^d.  des  Hupitaux,  6  Dec,  1907. 

94.  Grillot.     Lettres  a  M.  Calmette,  27  Juin  et  13  Juillet,  1907. 

95.  Gronow,  Grafe-Siimisch.     IL  Aufl.,  1  Abt.  S.  672. 

96.  Guerin.     Bee.  de  Med.  veterinaire  d'Alfort,  Aout,  1907. 

97.  Guerin  et  Delattre,     "Note  sur  I'opbtalmo-r^action  fi  la  tuberculine," 
Bull,  de  la  Soc.  de  Mid.  vet.,  18  Juillet,  1907. 


DIAGN(JSIS    OF    TUBEHCULOSIS  '    '203 

98.  Halipre  et  Hue.     Lettres  a  M.  Calraette,  22  Juiu  et  17  Juillet,  1907. 

99.  Hamburger.     Wien.  klin.  WocJienschr.,  1907,  Nr.  3G. 

100.  Hellborn.     Berl.  klin.  W'ochenschr.,  1907,  S.  893. 

101.  Holzkiiecht.  ''  Die  riintgenologische  Diagnostik  der  Erkrankungen 
der  Brusteingeweide,"  Hamburg,  1901. 

102.  Hutinel.  "  Effet  des  injections  sous-cutanees  de  tuberculine  chez  les 
enfants  tuberculeux,"  Sem.  medicale,  1895,  et  Congres  de  la  tuberculose,  Aout, 
1898. 

103.  loannovics  und  Kapsammer.  "  Unters.  iiber  die  Verwertbarkeit 
neuerer  Methodeu  zur  Diagnose  der  Tuberkulose  in  Tierversuch,"  Berl.  klin. 
Wochenschr.,  1907. 

104.  Kalt.     7  Okt.,  1907,  Ophthalm.  Ges.  zu  Paris. 

105.  Kentzler.  "  Uber  differenzierende  Kutan-Tuberkulinreaktion,"  Wien. 
kli7i.  Wochenschr.,  1908,  Xr.  1. 

106.  Klemperer,  F.      Ver.  f.  inn   Med.,  Berlin,  6.  I.,  1908. 

107.  Klieneberger.  "  Kritische  Bemerkungen  zur  klin.  Bedeutung  der 
Ophthalmoreaktion  auf  Tuberkulose,"  Mihich-.  med.  Wochenschr.,  Nr.  52,  1907. 

108.  Kliugmiiller.     •' Beitriige  zur  Tuberkulose  der  Haut,"  4rcft. /.  Dermal., 

1904,  Bd.  69,  und  Perl.  klin.  Wochenschr.,  1903,  Nr.  34. 

109.  Kolaczek  u.  Miiller.     Deutsche  med.  Wochenschr.,  1907,  Nr.  7  u.  18. 

110.  Kraus.     "  Zur  Kenntnis  des  Erythema  induratum,"  Arch.  f.  Dermaf., 

1905,  Bd.  76. 

111.  Kraus,  Lusenberger  und  Russ.      Wien.  klin.  Wochenschr.,  1907,  Nr.  45. 

112.  Krause-Hannover.     Zcitschr.  f.  Tuberk.,  Bd.  11,  H.  5. 

113.  Kronig.  "  Uber  masimale  Fiirbung  der  Tuberkelbazillen  im  Auswurf 
und  iiber  das  Anreicherungsverfahren,"  Med.  Klinik,  1907,  Nr.  24. 

114.     "  Friihdiagnose  der  Lungeutuberkulose,"  Deutsche  Klinik,  1907 

(Urban  u.  Schwarzenberg). 

115.     "  Zur   Topographie   der    Lungenspitzen    und   ihre   Perkussion  "' 

Berl.  klin.  Woche7tschr.,  1889,  N.  34. 

116.  Labbe.     "  Tuberculino-diagnostic,"  Gaz.  des  H6pitaux,  Juillet,  1907. 

117.  Landau.     Berl.  med.  Ges.,  8.  V.,  1907. 

118.  Lapersonne  s.  "Pariser  Brief,"  Berl.  klin.  Wochenschr.,  1908,  Nr.  2. 

119.  Leber.  "Die  Zirktilation  und  Ernahrungsverhaltnisse  des  Auges,"  in 
Griife-Samisch,  "  Handb.  d.  Augenheilk,'"  Bd.  II.,  2. 

120.  Lemaire  (Jules).  "  La  tuberculintest  de  Calmette  et  la  tuberculine  de 
rinstitut  Pasteur,  employees  pour  roculo-reaction.  La  cuti-reaction  a  la  tuber- 
culine dans  la  tuberculose  a  marche  rapide.  Remarques  sur  deux  cas  de  cuti- 
reaction,"  Comptes  rendus  hebd.  de  la  Soc.  de  Biol.,  T.  63,  No.  29. 

121.     "Note  sur    quelques  points  particuliers  de  la  cutireaction  a  la 

tuberculine,"  Comptes  rendus  hebd.  de  la  Soc.  de  Biol.,  T.  63,  No.  28,  1907. 

122.  Lemerre.      Soc.  de  Pediatric,  15  Oct.,  1907. 

123.  Lenhartz.  "  Uber  Erfahrungen  mit  der  Calmetteschen  Ophthalmo- 
reaktion und  der  von  Pirquetschen  kutanen  Tuberkulinprobe,"  Arztl.  Verein 
Hamburg,  29.  X.,  1907,  Miinch.  med.  Wochenschr.,  1907,  Nr.  48. 

124.  Lepine  (Jean).  "  Ophtalmo-reaction  en  Psychiatric,"  -Soc.  de  Biol., 
27  Juillet,  1907,  No.  27,  28,  29. 

125.  Lepine  et  R.  Charpenel.  "  Nouvelles  recherches  sur  I'ophtalmo- 
reaction  chez  les  alienes,"  Soc.  de  Biol.,  1907,  No.  28. 

126.  Lesne.     "Sur  I'ophtalmo-reaction,"  S.  d.  H.  6.  X.,  1907. 

127.  Lesne  et  Slarre.     La  Clinique,  30  .\out,  1907. 


204  THE  OPHTHALMIC  AND  CUTANEOUS 

128.  Letulle  (Paris).     Soc.  Mid.  Hop.,  28  Juin,  1907  ;  Soc.  de  Biol,  1907. 

129.     Cit.,  Soc.  de  Biol.,  1907  ;  Sem.  mi'd.,  1907,  No.  27. 

130.  Levy,  Fritz.  "  Uber  konjunktivale  Tuberkulinrealition."  Verein  fur 
innere  Medizin,  16.  12.  1907.     Deutsche  med.  Wochenschr.,  1908,  Nr.  3. 

131.  Levy.     "  Orvosi  Hetilap,"  1907,  No.  46. 

132.  Lignieres.  "  Sur  un  nouveau  mode  de  reaction  de  la  peau  a  la  tuber- 
culine  et  son  utilisation  dans  le  diagnostic  de  la  tuberculose."  Acad,  des  Sciences, 
Paris,  28  Oct. 

138.     Lignieres  u.  Berger.     Acad,  des  Sciences,  28.  X.,  1907. 

134.  Lowenstein.  "  tjber  die  intrazellulare  Lagerung  der  Tuberkelbazillen 
im  Sputum  und  ibre  prognostische  Bedeutung. "  Deutsclie  vied.  Wochenschr., 
1907,  Nr.  43. 

135.    Zeitschr.  f.  Tnberk.,  Bd.  5,  Heft  6. 

136.  Mainini.     "  Haut- und  Opbthalmoreaktion  auf  Tuberkulin."     Miinch. 
ed.   Wochenschr.,  Nr.  52,  1907. 

137.     Arztl.  Verein  Miincben,  10.   7.  1907,  Miinch.  med.    Wochenschr. 

1907,  Nr.  43. 

138.  Mantoux,  Congres  de  Medecine  de  Paris,  Octobre,  1907,  ref.  Miinch. 
med.  Wochenschr.,  1907,  Nr.  49. 

139.  Marie  et  Bourillet.  "  Opbtalmo-reaction  chez  les  alienes,"  Comptes 
rendtis  hebd.  de  la  Soc.  deBioL,  1907,  T.  62,  No.  27. 

140.  Marzagalli  und  Figari,  Ann.  del  Istituto  Maragliano,  1904,  H.  1. 

141.  Masenti.     "  Tuberkulinaugenreaktion,"  Rif.  med.,  1907,  No.  46. 

142.  Metraux.     Bev.  mid.  de  la  Suisse  romande,  20  Aout,  1907. 

143.  Meisser.  "  tJber  die  friihe  Erkennung  der  Lungentuberkulose," 
Therap.  Monatsh.,  Nov.,  1898. 

144.  Micbaelides,  Bremer's  Beitr. ,  1907,  Bd.  8,  H.  1 . 

144o.  Beitrdge  zur  Klinik  der  Tuherkulosc ,  Bd.  ix.  H.  1. 

145.  Micbeli  ed  Omarelli.  "  lusensibilita  locale  provocata  dalla  tuber- 
culina,"  Acad,  di  medic,  di  Torino,  29.  XI.,  1907. 

146.  Moller.  "  Le  traitement  de  la  tuberculose  dans  les  sanatoria,"  Con- 
gres de  Paris,  1906. 

147.  Mongour  et  Brandeis  (Bordeaux).  "Cytologic  de  I'exsudat  dans 
rOphtalmo-reaction  a  la  tuberculine. "     Bulletin  medical,  6  Novembre,  1907. 

148.  Mongour  et  Lande  (Bordeaux).     Bulletin  medical,  4  Septembre,  1907. 

149.  Montagnon.  "  L'Ophtalmo-reaction  a  la  tuberculine,"  Prov.  midicale, 
20  Juillet,  1907. 

150.  Morax.     Soc.  des  Hup.,  6.  XII.,  1907. 

151.  Moro.  Arztl.  Verein  in  Miinchen,  10.  7.  1907,  ref.  in  Wien.  klin. 
Wochenschr.,  1907. 

152.  Moro  und  Doganoff.  "Zur  Patbogenese  gewisser  Integumentverau- 
derungen  bei  Skrofulose,"  Wien.  klin.  Wochenschr.,  1907,  Nr.  31. 

153.  Moussu.  "  Cuti-reaction  a  la  tuberculine,"  Bull.  Soc.  cent,  de  Med.  vtit., 
18  Juillet,  1907  ;  Sem.  mid.,  1907,  No.  49. 

154.  Mouton  (Lissabon).     A  Medicina  contemporanea,  4  Aout,  1907. 

155.  Mucb.  "  Uber  die  nicbt  siiurefesten  Formen  des  Kocbschen  Tuberkel- 
bazillus.     Beitr.  z.  Klinik  d.  Tuberkulose,  Bd.  8,  H.  4.  Wxirzburg,  Stuber's  Verlag. 

156.  Miiller,  E.  "  Proteolytifcbe  Fermentwirkuugen  der  Leukozyteu  : 
neue  einfacbe  Verfabren  zur  rascben  Unterscbeidung  zwiscben  tuberkulosen  und 
andersartigen  Eiterungea,"  Deutsche  med.  Wochenschr.,  1907,  Nr.  44. 

157.  Miiller  u.  Jocbmann.     Munch,  med.  Wochenschr.,  1900,  Nr.  29. 

158.  Nagelscbmidt.     Deutsche  med.  Wochenschr.,  1907,  Nr.  40. 
Nicolai,  A.,  Bibin.     Inaugural  Dissertation,  Berlin,  1907. 


DIAGNOSIS    OF    TUBERCULOSIS  205 

100.     Nobecourfc  et  Mantoux.      "  Ophfcalmo-  et  cuti-reaction  dans  la  tuber- 
culose  experimentale  du  lapin,"  Soc.  de  Biol.,  26  Oct.,  1907. 
161.     Nobl.      Wien.  klin.  Wochenschr . ,   1908,  Nr.  1,  S.  27. 

102.  Oestreich,  "Die  Perkussiou  der  Lungenspitzen,"  Zeitschr.  f.  klin. 
Med.,  1898,  Bd.  .35. 

163.  Oliner  et  Terras.  "  Cuti-roaction  ilia  tuberculine,  Ophtalmo-reactioa." 
Presse  mi'dic,  18  Sept.,  1907. 

164.  Oppenheim.  "  Uber  Hautveriluderungen  Erwaclisener  im  Anschlusse 
an  die  Pirquetsche  Reaktion,"      Wien.  klin.  Wochenschr.,  1907,  Nr.  32. 

165.  Painblan.     Soc.  de  Mod.  du  Nord,  Novembre,  1907. 

166.  Pappenheim.  "  Befund  von  Smegmabazillen  in  menschlichen  Lun- 
gen."     Berl.  klin.  Wochenschr.,  12.  IX.,  1898,  Nr.  37. 

167.  Penzoldt.  "Uber  den  Einfluss  der  Korperbewegung  auf  die  Tem- 
peratur  Gesunder  und  Kranker,"  Milnch.  med.  Wochenschr.,  1899,  Nr.  15,  und 
1903,  Nr.  1. 

168.  Petit.  "  Le  diagnostic  de  la  Tuberculo.se  par  rOphtalmo-reaction," 
1907,  Masson,  Paris. 

169.  Pfaundler.  Milnch.  Ges.  f.  Kinderheilk.,  14.  VI.,  1907,  ref.  Mon.  f. 
Kinderheilk.,  Bd.  6,  Nr.  3. 

170.  Pforinger  und  Bunz.  "Uber  das  Mass  der  Bewegung  bei  der  Behand- 
lung  der  Lungeutuberkulose,"  Milnch.  med.  Wochenschr.,  1907,  Nr.  2. 

171.  Pick.  Darstellung  der  Antigene,  in  Kraus-Levaditi,  "  Hdb.  der 
Technik  u.  Methodik  der  Immun-Porsch.,"  Juni,  1907,  S.  364. 

172.  Pigger.  "  Kiinstlicher  Pneumothorax  u.  opsonischer  Index,"  Beitr. 
zur  Klinik  d.  Tuberkulose,  Wiirzburg,  Stuber's  Verlag,  Bd.  8,  H.  4. 

173.  V.  Pirquet.  "  Diagnostische  Verwertung  der  Allergic,"  Wien.  klin. 
Wochenschr.,  1907,  Nr.  41,  S.  1271. 

174.     "Der  diagnostische   Wert  der   kutanen  Tuberkulinreaktion    bei 

der  Tuberkulose  des  Kindesalters  auf  Grund  von  100  Sektionen,"  Wien.  klin. 
Wochenschr.,  1907,  Nr.  28,  S.  1369-1374,  und  Wien.  vied.  Wochenschr.,  1907, 
Nr.  28. 

175.     8.  v.,  1907,  Berl.  med.   Gesellsch.  :    "Uber  Tuberklinimpfung, 

15.  v.,  1907.  Berl.  med.  Gesellsch:  "Demonstration  zur  Tuberkulindiagnose 
durch  Hautimpfung,"  Berl.  klin.  Wochenschr.,  Nr.  22-23. 

176.     "Tuberkulindiagnose     durch     kutane     Impfung,"     Berl.      klin. 

Wochenschr.,  20.  Mai,  1907. 

177.     "1st    die    vakzinale    Friihreaktion     spezifisch  ? "      Wien.     klin. 

Wochenschr.,  1906,  Nr.  47. 

178.      "Der   diagnostische  Wert   der   kutanen  Tuberkulinreaktion   bei 

der  Tuberkulose  des  Kindesalters  auf  Grund  von  100  Sektionen,"  Wien.  klin. 
Wochenschr.,  1907,  Nr.  38. 

179.     "  Die   kutane   Tuberkuliuprobe,"    Verh.    der   24.    Vers.    d.    Ges. 

f.   Kinderh.,  Dresden,  1907,  Vers,  der  Naturf.  u.  Arzte. 

180.  ProufE.     Lettres  a  M.  Calmette,  25  Juin,  4  Juillet,  1907. 

181.  Putreys  et  Stiennon.     Soc.  de  Biol.,  1907,  No.  27. 

182.  Rabinowitsch.  "Befuud  von  siiurefesten  tuberkelbazillenahnlichen 
Bakterien  bei  Lungengangraa,"DeM^sc/^e  med.  WocJienschr.,  19.  IV.,  1900,  Nr.  16. 

183.     Berl.  klin.  Wochenschr.,  1907,  Nr.  2. 

184.  Railliet.     Revue  qin^rale  de  la  Tiiberculose,  .\out,  1907. 

185.  Rappaport.     Milnch.  med.  Wochenschr.,  1906,  Nr.  5. 

186.  R^non.     "  Sur  lophtalmo-reaction."     Soc.  des  Hop.,  6.  12.  1907. 


206  THE    OPHTHALMIC    AND    CUTANEOUS 

187.  Richet.     Soc.  de  Biol,  1902,  p.  170. 

188.  Rieder.  "  Zur  Diagaose  der  chronischeu  Luageutuberkulose  durch 
das  radiologischeVerfahrea,"  Fortschritte  auf  deiii  Gebiete  der  Runtgenstrahlen, 
VII.,  S.  1. 

189.  Rosenau  uud  Anderson.    Washington  Government  Printing  Office,  1906. 

190.  Rotch  und  Floyd.  "  Der  opsonische  Index  und  der  Tuberkulintest 
in  der  Diagnose  der  Behandluug  der  Friihtuberkulose,"  Journ.  Am.  Med.  Assoc, 
Chicago,  No.  8  ;  ref.  in  Miinch.  uied.  Wochensclir.,  Nr.  48. 

191.  Sabrazes  et  Duperie.    Gaz.  hebd.  des  Sc.  med.  de  Bordeaux,  Juillet,  1907. 

192.  Sahli.  "  Traitement  de  la  tuberculose  par  la  tuberculine,"  Lemoigne, 
editeur,  1907. 

193.  Salvolini.     "  Tuberkulin-Augeureaktion,"  Rif.  med.,  1907,  No.  42. 

194.  Schenk  u.  Seifert.  "Die  diagnostische  Bedeutung  der  Ophthalmo- 
reaktion  bei  Tuberkulose,"  Miinch.  med.  Woclienschr.,  1907,  Nr.  46. 

195.     "  tJber  die  diagn.  Bedeutung  der  Koujunktivalreaktion,"  Z)e^^tec7^e 

med.  Wochensclir.,  1898,  Nr.  2. 

196.  Schick.     Vers.  d.  Naturf.  Arzte,  Kassel,  1903. 

197.  Schirmer.  "  Die  sympathische  Augeuerkraukung,"  Grafe-Saniisch, 
"Handb.,"Bd.  6. 

198.  Schleissner.  "  Uber  d.  allergische  Reaktiouals  Hilfsmittel  der  Diagnose 
bei  Tuberkulose  im  Kindsalter,"  Verein  d.  Arzte  in  Prag,  30.  X.,  1907,  ref. 
in  Wien.  klin.  Wochenschr.,  1907,  Nr.  48. 

199.  Schmidt,  Ad.  "  Zur  Behandl.  der  Lungenphthise  mit  kiinstlichem 
Pneumothorax,"  Deutsche  med  Wochenschr.,  1906,  Nr.  13. 

200.  Schniitgeri.  "  Die  BeschafEenheit  der  im  Harn  bei  Morbus  Brightii 
vorkommenden  Leukozyten,"  Berl.  klin.  Wochenschr.,  1907,  Nr.  45. 

201.  Schrotter.  "  tJber  Anzeigepflicht  bei  Tuberkulose,"  Wien.  klin. 
Wochenschr. ,  1907,  Nr.  38. 

202.  Schubert.  "  Ophthalmoreaktiou  bei  Tuberkulose,"  Gesellsch.  f.  Natur- 
u.  Heilkunde  Dresden.     Miinch.  med.  Wochenschr.,  1907,  Nr.  50, 

203.  Senator.  "  Farbenanalytische  Uutersuchungen  der  Harnsedimeute  bei 
Nephritis,"  Virchoio's  Arch.,  Bd.  131,  3.  Heft. 

204.  Sicard.  "  De  I'emploi  de  la  tuberculine  pour  le  diagnostic  de  la  tuber- 
calose,"  Soc.  vied.  Hup.,  28  Juin,  1907  ;  Sein.  med.,  1907,  p.  323. 

205.  Sirakoff.     Zeitschr.  f.  Tuberkulose,  Bd.  11,  H.  5. 

206.  Sirot.     Congres  de  la  Tuberculose,  Aoi\t,  1898. 

207.  Slatineanu.  Bull.  List.  Past.,  30  Aout,  1907,  et  Rec.  de  Med.  ve'tcr. 
d'Alfort,  August,  1907. 

208.  Souques.     "  Sur  I'ophtalmo-reaction,"  Soc.  des  Hup.,  6.   12.   1907. 

209.  Soulier.     Bulletin  mi'dical,  14  Aout,  1907. 

210.  Stadelmann.  "  Uber  kutane  und  konj.  Tuberkulinreaktion."  II.  Tail. 
Klinische  Beobachtungen.     Verein  f.  inn.  Med.,  6  Jan.  1908. 

211.  Stephenson  (Sydney).  "The  Calmette  Serum  Reaction  in  Ophthal- 
mology."    Brit.  Med.  Jotirn.,  Oct.,  1907,  p.  2442. 

212.  Sticker.  "  Beitrag  zur  Diagnostik  der  tuberkulusen  Lungenaffektionen 
und  zur  regionaren  Beeinflussung  derselben,"  Zentralbl.  f.  klin.  Med.,  1891, 
Nr.  3. 

213.  Stock.  "Tuberkulose  als  iitiol.  chron.  Entziindungen,"  Gi'iife's  Arch. 
Bd.  66,  1. 

214.  Striimpell.     "  Lehrb.  der  iunereu  Medizin,"  Vogel,  Leipzig. 

215.  Stiirtz,  Metz,  4.    Vers,  der  Tuberkulose-Arzte,  24.  u.  25.  Mai,  1907. 

216.  Treupel.     Miinch.  med.    Wochenschr.,  1908,  Nr.  2. 


DIAGNOSIS    OF   TUBERCULOSIS  207 

•217.     Uriarte.     Semana  Mihlica,  Nr.  33,  1904. 

'218.     Valine.     "  Siir  un  noiiveau  precede  de  diagnostic  experimental  de  la 
tuberculosa,"  Acad,  des  Sciences,  3  et  17  .Juin,  1907. 

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Wochenschr. ,  1907. 


Table  I. 


Ocular  4.     '/i«  Immersion. 
Ivymplioiyte  sputum  with  tubercle  bacilli.     Prot.  :J797. 


Ocular  5.     '/n  bom.  Immersion. 
Lymphocyte  sputum  in  suspected  apices.     Prot.  3771. 


Ocular  2.     '  u  horn,  immersion. 
S))utum  with  lymphocytes  and  tubercle  bacilli. 


#• 


^  • 


•  •ivy  • 


m 


Ocular  5.     '/i«  immersion. 
Pleural  exudation  containing  lymphocytes.     Loffler. 


Lymphocyte  sputa  and  their  diagnostic  significance  (see  text.) 
Wol  ff- Eisne  r,  The  Ophthahnic  and  Cutaneous  Diagnoses  of  Tuberculosis. 


I'lhn  Balp,  Sons  &   Daiiulssim.   Ltd.,  London. 


Tabu  II. 


01 


&  ^) 


'^'«^v 


Ocular  2.     '/n  Immersion. 
Tbc.     Lymphocyte  exudation.     Tracid. 


t  cells.      Giant  cells 


Giant  ci 

:::a5Sfe.-.. 


OjO     O  /  o 


4 


riant  cells. 


Papule  of  lasting  reaction  produced  by  the  cutaneous  application  of  tuberculin; 
according  to  a  preparation  kindly  lent  by  Herr  Daels. 

Wolff-Eisner,  The  Ophthalmic  and   Cutaneous  Diagnoses  of  Tuberculosis. 


John  Bale,  Sons  &  Danielsson,   Ltd.,  London. 


L  006  775  328  5 


L  006  775  328  5 


